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1.
High Blood Press Cardiovasc Prev ; 27(4): 299-308, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32572706

RESUMO

Large conductive arteries undergo to structural modifications by aging, eventually leading to increased vascular stiffness. As consequence, cardiovascular hemodynamic changes by increasing central blood pressure which may be also associated to the remodelling of peripheral resistance arteries that contribute to increase further the central vascular stiffness and blood pressure. These modifications resemble the ones that has been shown in essential hypertension, thus a condition of "early vascular aging" has been described in hypertensive patients. Since hypertension related target organs, particularly the heart, face aortic blood pressure rather than brachial blood pressure, it has been recently suggested that central blood pressure and other parameters of large arteries' stiffness, including pulse wave velocity (PWV), may better correlate with subclinical organ damage and might be useful to assess the cardiovascular risk of patients beyond the traditional risk factors. Different devices have been validated to measure central blood pressure and PWV, and are currently available for clinical use. The increasing application of these tools in clinical practice could improve the management of hypertensive patients by better defining the cardiovascular risk and address the antihypertensive therapy.


Assuntos
Envelhecimento , Aorta/fisiopatologia , Pressão Arterial , Hipertensão/fisiopatologia , Remodelação Vascular , Rigidez Vascular , Fatores Etários , Animais , Anti-Hipertensivos/uso terapêutico , Aorta/efeitos dos fármacos , Pressão Arterial/efeitos dos fármacos , Humanos , Hipertensão/diagnóstico , Hipertensão/tratamento farmacológico , Hipertensão/epidemiologia , Prognóstico , Medição de Risco , Fatores de Risco , Fatores de Tempo , Remodelação Vascular/efeitos dos fármacos , Rigidez Vascular/efeitos dos fármacos
2.
Cardiovasc Pathol ; 49: 107230, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32585603

RESUMO

PURPOSE: Restenosis is the main complication after percutaneous coronary intervention. The proliferation of new intima contributes to the process. In this study, we aimed to explore the effect of olmesartan on intimal thickening after balloon injury and possible mechanism. METHODS: Aortic endothelial denudation model was made by a 2F balloon catheter. Thirty-six rats were randomly allocated into three groups: Control (n = 12) Surgery (n = 12, received vascular balloon injury) and Olmesartan (n = 12, received 3 mg.kg-1.d-1olmesartan after injury). Fourteen and 28 days after injury, HE staining was used to assess the aortic endothelial injury. Radioimmunological method was used to examine the level of angiotensin II (Ang II). Western blotting and reverse transcription polymerse chain reaction (RT-PCR) were employed to detect the protein and mRNA level of Apelin/APJ. RESULTS: After vascular balloon injury, the proliferation of vascular smooth muscle cells and the intimal thickening were increased. The mRNA and protein level of Ang II, AT1, Apelin and APJ mRNA were promoted by vascular balloon injury. Olmesartan decreased the proliferation of vascular smooth muscle cells and the intimal thickening. Olmesartan decreased the expression of Ang II and AT1, but further increased the expression of Apelin and APJ. Balloon injury also induced the activation of Extracellular signal-regulated kinase (ERK) signaling and olmesartan decreased the effect. CONCLUSION: Olmesartan inhibits the intimal thickening through activating Apelin/APJ and inhibiting AngII-AT1 and ERK pathway.


Assuntos
Bloqueadores do Receptor Tipo 1 de Angiotensina II/farmacologia , Receptores de Apelina/metabolismo , Apelina/metabolismo , Imidazóis/farmacologia , Músculo Liso Vascular/efeitos dos fármacos , Miócitos de Músculo Liso/efeitos dos fármacos , Neointima , Tetrazóis/farmacologia , Lesões do Sistema Vascular/tratamento farmacológico , Angioplastia com Balão , Angiotensina II/metabolismo , Animais , Aorta/efeitos dos fármacos , Aorta/lesões , Aorta/metabolismo , Aorta/patologia , Proliferação de Células/efeitos dos fármacos , Constrição Patológica , Modelos Animais de Doenças , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Masculino , Músculo Liso Vascular/lesões , Músculo Liso Vascular/metabolismo , Músculo Liso Vascular/patologia , Miócitos de Músculo Liso/metabolismo , Miócitos de Músculo Liso/patologia , Fosforilação , Ratos Wistar , Receptor Tipo 1 de Angiotensina/metabolismo , Transdução de Sinais , Lesões do Sistema Vascular/etiologia , Lesões do Sistema Vascular/metabolismo , Lesões do Sistema Vascular/patologia
3.
Nat Commun ; 11(1): 2622, 2020 05 26.
Artigo em Inglês | MEDLINE | ID: mdl-32457361

RESUMO

Vascular disease remains the leading cause of death and disability, the etiology of which often involves atherosclerosis. The current treatment of atherosclerosis by pharmacotherapy has limited therapeutic efficacy. Here we report a biomimetic drug delivery system derived from macrophage membrane coated ROS-responsive nanoparticles (NPs). The macrophage membrane not only avoids the clearance of NPs from the reticuloendothelial system, but also leads NPs to the inflammatory tissues, where the ROS-responsiveness of NPs enables specific payload release. Moreover, the macrophage membrane sequesters proinflammatory cytokines to suppress local inflammation. The synergistic effects of pharmacotherapy and inflammatory cytokines sequestration from such a biomimetic drug delivery system lead to improved therapeutic efficacy in atherosclerosis. Comparison to macrophage internalized with ROS-responsive NPs, as a live-cell based drug delivery system for treatment of atherosclerosis, suggests that cell membrane coated drug delivery approach is likely more suitable for dealing with an inflammatory disease than the live-cell approach.


Assuntos
Aterosclerose/tratamento farmacológico , Citocinas/metabolismo , Sistemas de Liberação de Medicamentos , Macrófagos/metabolismo , Nanopartículas/metabolismo , Animais , Aorta/efeitos dos fármacos , Aorta/metabolismo , Aterosclerose/metabolismo , Atorvastatina/uso terapêutico , Materiais Biomiméticos , Membrana Celular/metabolismo , Liberação Controlada de Fármacos , Feminino , Camundongos , Células RAW 264.7 , Espécies Reativas de Oxigênio/metabolismo , Resultado do Tratamento
4.
Toxicol Appl Pharmacol ; 400: 115041, 2020 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-32428593

RESUMO

Respiratory ailments have plagued occupational and public health communities exposed to World Trade Center (WTC) dust since the September 11, 2001 attack on the Twin Towers in Lower Manhattan. We proposed that these ailments were proposed to be induced by inhalation exposure to WTC particulate matter (WTCPM), that was released during the collapse of the buildings and its subsequent resuspension during cleanup. We investigated this hypothesis using both an in vitro and an in vivo mouse intranasal (IN) exposure models to identify the inflammatory potential of WTCPM with specific emphasis on respiratory and endothelial tissue responses. The in vitro exposure studies found WTCPM exposure to be positively correlated with cytotoxicity and increased NO2- production in both BEAS-2B pulmonary epithelial cells and THP-1 macrophage cells. The in vivo C57BL/6 mouse studies found significant increases in inflammatory markers including increases in polymorphonuclear neutrophil (PMN) influx into nasal and bronchoalveolar lavage fluids (NLF and BALF), as well as increased levels of total protein and cytokine/chemokines levels. Concurrently, NLF, BALF, and serum NO2- levels exhibited significant homeostatic temporal deviations as well as temporal myograohic aortic dysfunction in myography studies. Respiratory exposure to- and evidence -based retention of- WTCPM may have contributed to chronic systemic effects in exposed mice that r resembled to observed effects in WTCPM-exposed human populations. Collectively, these findings are reflective of WTCPM exposure and its effect(s) on respiratory and aortic tissues, highlighting potential dysfunctional pathways that may precipitate inflammatory events, while simultaneously altering homeostatic balances. The tight interplay between these balances, when chronically altered, may contribute to- or result in- chronically diseased pathological states.


Assuntos
Poluentes Atmosféricos/toxicidade , Materiais de Construção/toxicidade , Poeira/análise , Endotélio Vascular/efeitos dos fármacos , Exposição por Inalação/efeitos adversos , Pneumonia/induzido quimicamente , Poluentes Atmosféricos/análise , Animais , Aorta/efeitos dos fármacos , Aorta/fisiopatologia , Biomarcadores/sangue , Líquido da Lavagem Broncoalveolar/química , Líquido da Lavagem Broncoalveolar/citologia , Líquido da Lavagem Broncoalveolar/imunologia , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Materiais de Construção/análise , Endotélio Vascular/fisiopatologia , Humanos , Exposição por Inalação/análise , Pulmão/efeitos dos fármacos , Pulmão/imunologia , Camundongos Endogâmicos C57BL , Cavidade Nasal/efeitos dos fármacos , Cavidade Nasal/imunologia , Cidade de Nova Iorque , Ataques Terroristas de 11 de Setembro , Células THP-1
5.
Toxicol Appl Pharmacol ; 400: 115070, 2020 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-32464219

RESUMO

Vascular dysfunction plays a critical role in the pathogenesis of sepsis. We elucidated the mechanisms underlying the amelioration of lipopolysaccharide (LPS)-induced vascular inflammation by oroxylin A (OroA) post-treatment in rats. The animals were intraperitoneally injected with LPS (10 mg/kg) to induce systemic inflammation and intravenously (iv) administered OroA (15 mg/kg) 6 h after the LPS treatment. The assessments included biochemical changes in peripheral blood, vascular reactivity which was evaluated by blood-vessel myography, morphological/histological assessment of inflammation, toll-like receptor (TLR)-4-mediated interleukin-1-receptor-associated-kinase (IRAK)-4 activation, changes in adhesion molecule expression, and endothelial junctional stability in the aorta. LPS significantly enhanced the proinflammatory cytokine release, increased vascular cell adhesion molecule (VCAM)-1 expression, disrupted endothelial tight junction, reduced vascular endothelial barrier stability, and increased macrophage infiltration and accumulation in the aorta. All observed pathological changes and vascular inflammation were significantly reversed by the OroA post-treatment. Importantly, OroA suppressed the increased adhesion molecule expression and the endothelial barrier disruption by inhibiting LPS-activated IRAK-4-targeted inhibitory nuclear factor kappa B kinase (IKK) α/ß complex phosphorylation, without directly affecting the interaction between LPS and TLR-4. Moreover, the iNOS activity induced by the LPS challenge was inhibited by the OroA pretreatment of the isolated aortic rings. These results suggest that OroA regulates the vascular tone by inhibiting vascular hyporeactivity caused by NO overproduction and reverses the endothelial barrier dysfunction and inflammation by inhibiting the IRAK-4-mediated IKKα/ß phosphorylation. Overall, these findings suggest OroA administration as a potentially useful therapeutic approach for clinical interventions in septic shock.


Assuntos
Aorta/efeitos dos fármacos , Endotélio Vascular/efeitos dos fármacos , Flavonoides/farmacologia , Sepse/prevenção & controle , Molécula 1 de Adesão de Célula Vascular/genética , Animais , Aorta/imunologia , Aorta/patologia , Células Cultivadas , Quimiocina CCL2/sangue , Citocinas/sangue , Modelos Animais de Doenças , Células Endoteliais/efeitos dos fármacos , Células Endoteliais/metabolismo , Células Endoteliais/patologia , Endotélio Vascular/imunologia , Endotélio Vascular/patologia , Endotoxinas/farmacologia , Flavonoides/uso terapêutico , Expressão Gênica/efeitos dos fármacos , Masculino , Infiltração de Neutrófilos/efeitos dos fármacos , Ratos Sprague-Dawley , Sepse/sangue , Sepse/patologia
6.
Artigo em Inglês | MEDLINE | ID: mdl-32243768

RESUMO

Cardiovascular disease is a major cause of morbidity and mortality among patients with chronic kidney disease (CKD). Trimethylamine-N-oxide (TMAO), a uremic metabolite that is elevated in the setting of CKD, has been implicated as a nontraditional risk factor for cardiovascular disease. While association studies have linked elevated plasma levels of TMAO to adverse cardiovascular outcomes, its direct effect on cardiac and smooth muscle function remains to be fully elucidated. We hypothesized that pathological concentrations of TMAO would acutely increase cardiac and smooth muscle contractility. These effects may ultimately contribute to cardiac dysfunction during CKD. High levels of TMAO significantly increased paced, ex vivo human cardiac muscle biopsy contractility (P < 0.05). Similarly, TMAO augmented contractility in isolated mouse hearts (P < 0.05). Reverse perfusion of TMAO through the coronary arteries via a Langendorff apparatus also enhanced cardiac contractility (P < 0.05). In contrast, the precursor molecule, trimethylamine (TMA), did not alter contractility (P > 0.05). Multiphoton microscopy, used to capture changes in intracellular calcium in paced, adult mouse hearts ex vivo, showed that TMAO significantly increased intracellular calcium fluorescence (P < 0.05). Interestingly, acute administration of TMAO did not have a statistically significant influence on isolated aortic ring contractility (P > 0.05). We conclude that TMAO directly increases the force of cardiac contractility, which corresponds with TMAO-induced increases in intracellular calcium but does not acutely affect vascular smooth muscle or endothelial function of the aorta. It remains to be determined if this acute inotropic action on cardiac muscle is ultimately beneficial or harmful in the setting of CKD.NEW & NOTEWORTHY We demonstrate for the first time that elevated concentrations of TMAO acutely augment myocardial contractile force ex vivo in both murine and human cardiac tissue. To gain mechanistic insight into the processes that led to this potentiation in cardiac contraction, we used two-photon microscopy to evaluate intracellular calcium in ex vivo whole hearts loaded with the calcium indicator dye Fluo-4. Acute treatment with TMAO resulted in increased Fluo-4 fluorescence, indicating that augmented cytosolic calcium plays a role in the effects of TMAO on force production. Lastly, TMAO did not show an effect on aortic smooth muscle contraction or relaxation properties. Our results demonstrate novel, acute, and direct actions of TMAO on cardiac function and help lay the groundwork for future translational studies investigating the complex multiorgan interplay involved in cardiovascular pathogenesis during CKD.


Assuntos
Coração/efeitos dos fármacos , Metilaminas/farmacologia , Contração Miocárdica , Idoso , Animais , Aorta/efeitos dos fármacos , Aorta/fisiologia , Feminino , Coração/fisiologia , Humanos , Masculino , Metilaminas/toxicidade , Camundongos , Pessoa de Meia-Idade , Músculo Liso/efeitos dos fármacos , Músculo Liso/fisiologia , Ratos , Ratos Sprague-Dawley
7.
Artigo em Inglês | MEDLINE | ID: mdl-32302491

RESUMO

Renovascular hypertension is characterized by activation of the renin-angiotensin-aldosterone system, blunted natriuretic responses, and elevated sympathetic nerve activity. Excess dietary salt intake exaggerates arterial blood pressure (ABP) in multiple models of experimental hypertension. The present study tested whether a high-salt diet exaggerated ABP and vascular dysfunction in a 2-kidney, 1-clip (2K1C) murine model. Male C57BL/6J mice (8-12 wk) were randomly assigned, and fed a 0.1% or 4.0% NaCl diet, and instrumented with telemetry units to measure ABP. Then, the 2K1C model was produced by placing a cuff around the right renal artery. Systolic, diastolic, and mean ABP were significantly higher in mice fed 4.0% vs. 0.1% NaCl at 1 wk but not after 3 wk. Interestingly, 2K1C hypertension progressively increased arterial pulse pressure in both groups; however, the magnitude was significantly greater in mice fed 4.0% vs. 0.1% NaCl at 3 wk. Moreover, pulse wave velocity was significantly greater in 2K1C mice fed 4.0% vs. 0.1% NaCl diet or sham-operated mice fed either diet. Histological assessment of aortas indicated no structural differences among groups. Finally, endothelium-dependent vasodilation was significantly and selectively attenuated in the aorta but not mesenteric arteries of 2K1C mice fed 4.0% NaCl vs. 0.1% NaCl or sham-operated control mice. The findings suggest that dietary salt loading transiently exaggerates 2K1C renovascular hypertension but promotes chronic aortic stiffness and selective aortic vascular dysfunction.NEW & NOTEWORTHY High dietary salt exaggerates hypertension in multiple experimental models. Here we demonstrate that a high-salt diet produces a greater increase in arterial blood pressure at 1 wk after induction of 2-kidney, 1-clip (2K1C) hypertension but not at 3 wk. Interestingly, 2K1C mice fed a high-salt diet displayed an exaggerated pulse pressure, elevated pulse wave velocity, and reduced endothelium-dependent vasodilation of the aorta but not mesenteric arteries. These findings suggest that dietary salt may interact with underlying cardiovascular disease to promote selective vascular dysfunction and aortic stiffness.


Assuntos
Hipertensão Renovascular/etiologia , Cloreto de Sódio na Dieta/efeitos adversos , Rigidez Vascular , Animais , Aorta/efeitos dos fármacos , Aorta/patologia , Aorta/fisiopatologia , Pressão Sanguínea , Endotélio Vascular/efeitos dos fármacos , Endotélio Vascular/patologia , Endotélio Vascular/fisiopatologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Cloreto de Sódio na Dieta/toxicidade , Vasoconstrição
8.
Arterioscler Thromb Vasc Biol ; 40(6): 1559-1573, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32321307

RESUMO

OBJECTIVE: Excessive prostaglandin E2 production is a hallmark of abdominal aortic aneurysm (AAA). Enhanced expression of prostaglandin E2 receptor EP4 (prostaglandin E receptor 4) in vascular smooth muscle cells (VSMCs) has been demonstrated in human AAAs. Although moderate expression of EP4 contributes to vascular homeostasis, the roles of excessive EP4 in vascular pathology remain uncertain. We aimed to investigate whether EP4 overexpression in VSMCs exacerbates AAAs. Approach and Results: We constructed mice with EP4 overexpressed selectively in VSMCs under an SM22α promoter (EP4-Tg). Most EP4-Tg mice died within 2 weeks of Ang II (angiotensin II) infusion due to AAA, while nontransgenic mice given Ang II displayed no overt phenotype. EP4-Tg developed much larger AAAs than nontransgenic mice after periaortic CaCl2 application. In contrast, EP4fl/+;SM22-Cre;ApoE-/- and EP4fl/+;SM22-Cre mice, which are EP4 heterozygous knockout in VSMCs, rarely exhibited AAA after Ang II or CaCl2 treatment, respectively. In Ang II-infused EP4-Tg aorta, Ly6Chi inflammatory monocyte/macrophage infiltration and MMP-9 (matrix metalloprotease-9) activation were enhanced. An unbiased analysis revealed that EP4 stimulation positively regulated the genes binding cytokine receptors in VSMCs, in which IL (interleukin)-6 was the most strongly upregulated. In VSMCs of EP4-Tg and human AAAs, EP4 stimulation caused marked IL-6 production via TAK1 (transforming growth factor-ß-activated kinase 1), NF-κB (nuclear factor-kappa B), JNK (c-Jun N-terminal kinase), and p38. Inhibition of IL-6 prevented Ang II-induced AAA formation in EP4-Tg. In addition, EP4 stimulation decreased elastin/collagen cross-linking protein LOX (lysyl oxidase) in both human and mouse VSMCs. CONCLUSIONS: Dysregulated EP4 overexpression in VSMCs promotes inflammatory monocyte/macrophage infiltration and attenuates elastin/collagen fiber formation, leading to AAA exacerbation.


Assuntos
Aneurisma da Aorta Abdominal/etiologia , Inflamação/etiologia , Músculo Liso Vascular/metabolismo , Receptores de Prostaglandina E Subtipo EP4/fisiologia , Transdução de Sinais/fisiologia , Angiotensina II/administração & dosagem , Animais , Aorta/efeitos dos fármacos , Aorta/metabolismo , Aorta/patologia , Aneurisma da Aorta Abdominal/patologia , Cloreto de Cálcio/administração & dosagem , Expressão Gênica , Regulação da Expressão Gênica/fisiologia , Humanos , Interleucina-6/genética , Macrófagos/patologia , Metaloproteinase 9 da Matriz/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Knockout para ApoE , Camundongos Transgênicos , Monócitos/patologia , Músculo Liso Vascular/química , Miócitos de Músculo Liso/metabolismo , Proteína-Lisina 6-Oxidase/análise , Proteína-Lisina 6-Oxidase/genética , Receptores de Citocinas/genética , Receptores de Prostaglandina E Subtipo EP4/genética
9.
Nutr Metab Cardiovasc Dis ; 30(5): 843-846, 2020 05 07.
Artigo em Inglês | MEDLINE | ID: mdl-32278610

RESUMO

BACKGROUND AND AIMS: Prospective epidemiological studies highlighted recently the link between artificial sweeteners (AS) consumption and the risk of developing cardiometabolic diseases. However, underlying mechanisms remain unknown. Thus, the aim of this preliminary study was to characterize, in a healthy rat population, the effect of chronic AS consumption on body composition and vascular function, an early marker for cardiovascular disease. METHODS AND RESULTS: Healthy Wistar rats followed a 10-week standard diet including the consumption of water sweetened or not with a sucralose/acesulfame potassium solution at different concentrations: for moderate consumption at 1 and 2 mg.kg-1.day-1, respectively or high intake at 15 and 15 mg.kg-1.day-1 for both molecules (acceptable daily intake). Body fat composition has been evaluated and ex vivo aortic vasomotor function has been investigated with a pharmacological approach. CONCLUSION: Both groups of AS-treated rats showed a significant increase in subcutaneous and perirenal adipose tissue mass storage, without changes in total body mass. However, rats that have consumed AS at Acceptable Daily Intake (ADI) concentration revealed a significant vascular endothelial dysfunction compared to other groups. These results are interesting because they will help to better explain the observed increase in cardiometabolic risk.


Assuntos
Aorta/efeitos dos fármacos , Endotélio Vascular/efeitos dos fármacos , Sacarose/análogos & derivados , Edulcorantes/toxicidade , Tiazinas/toxicidade , Vasodilatação/efeitos dos fármacos , Adiposidade/efeitos dos fármacos , Animais , Aorta/fisiopatologia , Relação Dose-Resposta a Droga , Endotélio Vascular/fisiopatologia , Dados Preliminares , Ratos Wistar , Gordura Subcutânea/efeitos dos fármacos , Gordura Subcutânea/fisiopatologia , Sacarose/administração & dosagem , Sacarose/toxicidade , Edulcorantes/administração & dosagem , Tiazinas/administração & dosagem
10.
Cardiovasc Ther ; 2020: 1926249, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32328171

RESUMO

Isoliquiritigenin (ISL) is a flavonoid isolated mainly from the licorice plant, a traditional Chinese herb. ISL has shown anticancer, anti-inflammatory, antioxidant, and antidiabetic activities. However, the pharmaceutical effects of ISL on atherosclerosis are seldom explored. In this study, we used apolipoprotein E (ApoE) knockout mouse model and angiotensin II- (Ang II-) stimulated vascular smooth muscle cells (VSMCs) to elucidate the pharmacological mechanism of ISL to inhibit atherosclerosis. We found that in ApoE-/- mice ISL could attenuate atherosclerotic lesion, reduce serum lipid levels, and inhibit TRPC5 expression. In vitro, ISL inhibited Ang II-stimulated proliferation of VSMCs and suppressed Ang II-induced TRPC5 and PCNA expressions in a dose-dependent fashion. In conclusion, our findings provide novel insight into the pharmacological effects of ISL on atherosclerosis and suggest that ISL is beneficial for cardiovascular protection.


Assuntos
Aorta/efeitos dos fármacos , Doenças da Aorta/prevenção & controle , Aterosclerose/prevenção & controle , Chalconas/farmacologia , Placa Aterosclerótica , Canais de Cátion TRPC/antagonistas & inibidores , Animais , Aorta/metabolismo , Aorta/patologia , Doenças da Aorta/genética , Doenças da Aorta/metabolismo , Doenças da Aorta/patologia , Aterosclerose/genética , Aterosclerose/metabolismo , Aterosclerose/patologia , Proliferação de Células/efeitos dos fármacos , Células Cultivadas , Modelos Animais de Doenças , Lipídeos/sangue , Camundongos Endogâmicos C57BL , Camundongos Knockout para ApoE , Músculo Liso Vascular/efeitos dos fármacos , Músculo Liso Vascular/metabolismo , Músculo Liso Vascular/patologia , Miócitos de Músculo Liso/efeitos dos fármacos , Miócitos de Músculo Liso/metabolismo , Miócitos de Músculo Liso/patologia , Antígeno Nuclear de Célula em Proliferação/genética , Antígeno Nuclear de Célula em Proliferação/metabolismo , Transdução de Sinais , Canais de Cátion TRPC/metabolismo
11.
Biol Pharm Bull ; 43(3): 493-502, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32115508

RESUMO

The ß-adrenoceptor (ß-AR)-mediated pharmacological effects of catecholamine (CA) metabolites are not well known. We examined the effects of seven CA metabolites on smooth muscle relaxation in mouse and guinea pig (GP) tracheas and rat thoracic aorta. Among them, metadrenaline (MA) significantly relaxed GP trachea (ß2-AR dominant), even in the presence of clorgiline, a monoamine oxidase-A inhibitor. In mouse trachea (ß1-AR dominant), normetadrenaline (NMA) and MA (10-4 M each) apparently did not affect isoprenaline (ISO)-induced relaxation, but significantly inhibited it in the presence of clorgiline. ISO-induced relaxation was also unaffected by 3,4-dihydroxyphenylglycol (DHPG) (10-4 M), but significant suppression was observed with the addition of 3,5-dinitrocatechol, a catechol-O-methyltransferase inhibitor. In GP trachea, NMA, MA, 3,4-dihydroxymandelic acid (DOMA), and DHPG (10-4 M each) significantly augmented ISO-induced relaxation. However, in the presence of clorgiline plus 3,5-dinitrocatechol, both NMA and MA (10-4 M) significantly suppressed ISO-induced relaxation. DHPG (10-4 M) also significantly suppressed ISO-induced relaxation in the presence of 3,5-dinitrocatechol. In rat thoracic aorta, DHPG (10-4 M) significantly suppressed relaxation induced by CGP-12177 A (a ß3-AR partial agonist) in the presence of 3,5-dinitrocatechol plus propranolol. Our findings indicate that 1) MA may possess ß2-AR agonistic action; 2) NMA and MA augment ß2-AR-mediated tracheal relaxation in the absence of CA metabolic inhibitors, though themselves possessing ß1-, ß2-AR antagonistic action (ß2 > ß1); 3) DHPG exhibits ß1-, ß2-, ß3-AR antagonistic action, and this is particularly marked for ß3-AR. Our observations may help explain some of the pathologies associated with pheochromocytoma, which is characterized by increased CA metabolite levels.


Assuntos
Agonistas Adrenérgicos beta/farmacologia , Antagonistas Adrenérgicos beta/farmacologia , Aorta/efeitos dos fármacos , Relaxamento Muscular/efeitos dos fármacos , Músculo Liso/efeitos dos fármacos , Traqueia/efeitos dos fármacos , Animais , Carbacol/farmacologia , Cobaias , Isoproterenol/farmacologia , Masculino , Camundongos , Propranolol/farmacologia , Ratos , Receptores Adrenérgicos beta/metabolismo , Receptores Adrenérgicos beta 2/metabolismo
12.
Cardiovasc Drugs Ther ; 34(2): 145-152, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32086626

RESUMO

OBJECTIVE: Increased myelopoiesis has been linked to risk of atherosclerotic cardiovascular disease (ACD). Excessive myelopoiesis can be driven by dyslipidemia and cholesterol accumulation in hematopoietic stem and progenitor cells (HSPC) and may involve increased signaling via Janus kinase 2 (JAK2). Constitutively activating JAK2 mutants drive biased myelopoiesis and promote development of myeloproliferative neoplasms (MPN) or clonal hematopoiesis, conditions associated with increased risk of ACD. JAK2 inhibitors have been developed as a therapy for MPNs. The potential for JAK2 inhibitors to protect against atherosclerosis has not been tested. We therefore assessed the impact of JAK2 inhibition on atherogenesis. METHODS: A selective JAK2 inhibitor TG101348 (fedratinib) or vehicle was given to high-fat high-cholesterol Western diet (WD)-fed wild-type (WT) or Apoe-/- mice. Hematopoietic cell profiles, cell proliferation, and atherosclerosis in WT or Apoe-/- mice were assessed. RESULTS: TG101348 selectively reversed neutrophilia, monocytosis, HSPC, and granulocyte-macrophage progenitor (GMP) expansion in Apoe-/- mice with decreased cellular phosphorylated STAT5 and ERK1/2 and reduced cell cycling and BrdU incorporation in HSPCs, indicating inhibition of JAK/STAT signaling and cell proliferation. Ten-week WD feeding allowed the development of marked aortic atherosclerosis in Apoe-/- mice which was substantially reduced by TG101348. CONCLUSIONS: Selective JAK2 inhibition reduces atherogenesis by suppressing excessive myelopoiesis in hypercholesterolemic Apoe-/- mice. These findings suggest selective JAK2 inhibition as a potential therapeutic approach to decrease ACD risk in patients with increased myelopoiesis and leukocytosis.


Assuntos
Aorta/efeitos dos fármacos , Doenças da Aorta/prevenção & controle , Aterosclerose/prevenção & controle , Células-Tronco Hematopoéticas/efeitos dos fármacos , Janus Quinase 2/antagonistas & inibidores , Inibidores de Janus Quinases/farmacologia , Mielopoese/efeitos dos fármacos , Pirrolidinas/farmacologia , Sulfonamidas/farmacologia , Animais , Aorta/enzimologia , Aorta/patologia , Doenças da Aorta/enzimologia , Doenças da Aorta/genética , Doenças da Aorta/patologia , Aterosclerose/enzimologia , Aterosclerose/genética , Aterosclerose/patologia , Proliferação de Células/efeitos dos fármacos , Células Cultivadas , Modelos Animais de Doenças , Feminino , Células-Tronco Hematopoéticas/enzimologia , Células-Tronco Hematopoéticas/patologia , Janus Quinase 2/metabolismo , Leucocitose/enzimologia , Leucocitose/prevenção & controle , Camundongos Endogâmicos C57BL , Camundongos Knockout para ApoE , Placa Aterosclerótica , Transdução de Sinais
13.
Biochem Biophys Res Commun ; 524(4): 853-860, 2020 04 16.
Artigo em Inglês | MEDLINE | ID: mdl-32046856

RESUMO

Telmisartan, an angiotensin II type 1 receptor blocker (ARB), is widely used to treat hypertension. Dysfunction of vascular smooth muscle cells (VSMCs) is well-established to contribute to the pathogenesis of various vascular diseases. A growing body of evidence indicates that increased VSMC contractility plays a primary role in the development of pathological artery spasms. Nevertheless, effect of telmisartan on VSMC contractility, and its mechanism of action remain unknown. Here, we investigated the mechanism by which telmisartan inhibits VSMC contractility and vessel contraction in rat VSMCs and endothelium-deprived aortas. Telmisartan inhibited phenylephrine-induced vessel contraction in endothelium-deprived aortas, and decreased myosin light chain kinase (MLCK) levels (without altering corresponding mRNA levels) and myosin light chain (MLC) phosphorylation at Ser19 (p-MLC-Ser19) in VSMCs. MG-132 but not doxycycline significantly restored telmisartan-inhibited MLCK expression and p-MLC-Ser19. Telmisartan induced AMP-activated protein kinase (AMPK) phosphorylation at Thr172 (p-AMPK-Thr172), and compound C or ectopic expression of the dominant negative (dn)-AMPKα1 gene significantly reversed telmisartan-inhibited MLCK expression and p-MLC-Ser19. Of the ARBs tested (including losartan and fimasartan), only telmisartan increased p-AMPK-Thr172, and inhibited MLCK expression and p-MLC-Ser19. GW9662 had no effects on telmisartan-induced changes. Similar to the in vitro results, telmisartan enhanced p-AMPK-Thr172, and inhibited MLCK expression and p-MLC-Ser19 in endothelium-deprived aortas. Furthermore, the telmisartan-inhibited vessel contraction in the aortas was significantly reversed by MG-132 or compound C. In conclusion, we demonstrated that telmisartan inhibits VSMC contractility and vessel contraction by activating AMPK/proteasome/MLCK degradation signaling axis. These results suggest that telmisartan can be used to treat pathological vasospasms.


Assuntos
Proteínas Quinases Ativadas por AMP/genética , Anti-Hipertensivos/farmacologia , Contração Muscular/efeitos dos fármacos , Miócitos de Músculo Liso/efeitos dos fármacos , Quinase de Cadeia Leve de Miosina/genética , Complexo de Endopeptidases do Proteassoma/efeitos dos fármacos , Telmisartan/farmacologia , Proteínas Quinases Ativadas por AMP/metabolismo , Animais , Aorta/citologia , Aorta/efeitos dos fármacos , Aorta/metabolismo , Doxiciclina/farmacologia , Regulação da Expressão Gênica , Leupeptinas/farmacologia , Masculino , Músculo Liso Vascular/citologia , Músculo Liso Vascular/efeitos dos fármacos , Músculo Liso Vascular/metabolismo , Miócitos de Músculo Liso/citologia , Miócitos de Músculo Liso/metabolismo , Quinase de Cadeia Leve de Miosina/metabolismo , Fenilefrina/antagonistas & inibidores , Fenilefrina/farmacologia , Fosforilação/efeitos dos fármacos , Cultura Primária de Células , Complexo de Endopeptidases do Proteassoma/metabolismo , Proteólise/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley , Vasoconstritores/antagonistas & inibidores , Vasoconstritores/farmacologia
14.
Vascular ; 28(4): 465-474, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32089109

RESUMO

OBJECTIVE: Calcification serves as a surrogate for atherosclerosis-associated vascular diseases, and coronary artery calcification is mediated by multiple pathogenic factors. Estrogen is a known factor that protects the arterial wall against atherosclerosis, but its role in the coronary artery calcification development remains largely unclear. This study tested the hypothesis that estrogen inhibits coronary artery calcification via the hypoxia-induced factor-1α pathway. METHODS: Eight-week-old healthy female Sprague-Dawley rats were castrated, and vitamin D3 was administered orally to establish. Hypoxia-induced factor-1 inhibitor was administered to test its effect on vascular calcification and expression of bone morphogenetic protein 2 and runt-related transcription factor-2. Vascular smooth muscle cell calcification was induced with CaCl2 in rat aortic smooth muscle cells in the presence or absence of E2(17ß-estradiol) and bone morphogenetic protein 2 siRNA intervention. RESULTS: The estrogen levels in ovariectomized rats were significantly decreased, as determined by ELISA. Expression of hypoxia-induced factor-1α mRNA and protein was significantly increased in vascular cells with calcification as compared to those without calcification (p < 0.01). E2 treatment decreased the calcium concentration in vascular cell calcification and cell calcium nodules in vitro (p < 0.05). E2 also lowered the levels of hypoxia-induced factor-1α mRNA and protein (p < 0.01). Oral administration of the hypoxia-induced factor-1α inhibitor dimethyloxetane in castrated rats alleviated vascular calcification and expression of osteogenesis-related transcription factors, bone morphogenetic protein 2 and RUNX2 (p < 0.01). Finally, bone morphogenetic protein 2 siRNA treatment decreased the levels of p-Smad1/5/8 in A7r5 calcification cells (p < 0.01). CONCLUSION: Estrogen deficiency enhances vascular calcification. Treatment with estrogen reduces the expression of hypoxia-induced factor-1α as well as vascular calcification in rats. The estrogen effects occur in a fashion dependent on hypoxia-induced factor-1α regulation of bone morphogenetic protein-2 and downstream Smad1/5/8.


Assuntos
Doenças da Aorta/prevenção & controle , Estradiol/farmacologia , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Músculo Liso Vascular/efeitos dos fármacos , Miócitos de Músculo Liso/efeitos dos fármacos , Calcificação Vascular/prevenção & controle , Animais , Aorta/efeitos dos fármacos , Aorta/metabolismo , Aorta/patologia , Doenças da Aorta/genética , Doenças da Aorta/metabolismo , Doenças da Aorta/patologia , Proteína Morfogenética Óssea 2/genética , Proteína Morfogenética Óssea 2/metabolismo , Linhagem Celular , Subunidade alfa 1 de Fator de Ligação ao Core/genética , Subunidade alfa 1 de Fator de Ligação ao Core/metabolismo , Modelos Animais de Doenças , Feminino , Subunidade alfa do Fator 1 Induzível por Hipóxia/genética , Músculo Liso Vascular/metabolismo , Músculo Liso Vascular/patologia , Miócitos de Músculo Liso/metabolismo , Miócitos de Músculo Liso/patologia , Ovariectomia , Fosforilação , Ratos Sprague-Dawley , Transdução de Sinais , Proteínas Smad Reguladas por Receptor/metabolismo , Calcificação Vascular/genética , Calcificação Vascular/metabolismo , Calcificação Vascular/patologia
15.
Braz J Med Biol Res ; 53(2): e9304, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32049102

RESUMO

Metabolic syndrome is a multifaceted condition associated with a greater risk of various disorders (e.g., diabetes and heart disease). In a rat model of metabolic syndrome, an acute in vitro application of rosuvastatin causes relaxation of aortic rings. Since the outcome of a subchronic rosuvastatin treatment is unknown, the present study explored its effect on acetylcholine-induced vasorelaxation of aortic rings from rats with metabolic syndrome. Animals were submitted to a 16-week treatment, including a standard diet, a cafeteria-style diet (CAF-diet), or a CAF-diet with daily rosuvastatin treatment (10 mg/kg). After confirming the development of metabolic syndrome in rats, aortic segments were extracted from these animals (those treated with rosuvastatin and untreated) and the acetylcholine-induced relaxant effect on the corresponding rings was evaluated. Concentration-response curves were constructed for this effect in the presence/absence of L-NAME, ODQ, KT 5823, 4-aminopyridine (4-AP), tetraethylammonium (TEA), apamin plus charybdotoxin, glibenclamide, indomethacin, clotrimazole, and cycloheximide pretreatment. Compared to rings from control rats, acetylcholine-induced vasorelaxation decreased in rings from animals with metabolic syndrome, and was maintained at a normal level in animals with metabolic syndrome plus rosuvastatin treatment. The effect of rosuvastatin was inhibited by L-NAME, ODQ, KT 5823, TEA, apamin plus charybdotoxin, but unaffected by 4-AP, glibenclamide, indomethacin, clotrimazole, or cycloheximide. In conclusion, the subchronic administration of rosuvastatin to rats with metabolic syndrome improved the acetylcholine-induced relaxant response, involving stimulation of the NO/cGMP/PKG/Ca2+-activated K+ channel pathway.


Assuntos
Acetilcolina/farmacologia , Aorta/efeitos dos fármacos , Endotélio Vascular/efeitos dos fármacos , Síndrome Metabólica/fisiopatologia , Rosuvastatina Cálcica/farmacologia , Vasodilatação/efeitos dos fármacos , Animais , Modelos Animais de Doenças , Endotélio Vascular/fisiopatologia , Masculino , Ratos , Ratos Wistar , Vasodilatadores
16.
Int. j. morphol ; 38(1): 215-221, Feb. 2020. graf
Artigo em Inglês | LILACS | ID: biblio-1056424

RESUMO

The potential inhibitory effect of the insulin mimicking agent, vanadium on type 2 diabetes mellitus (T2DM)induced alterations to the aorta ultrastructure associated with the suppression of dyslipedima and biomarkers of inflammation has not been investigated before. Therefore, we tested whether vanadium can protect against aortic injury induced secondary to T2DM possibly via the inhibition of blood lipid and inflammatory biomarkers. T2DM was induced in rats by a high-fat diet and streptozotocin (50 mg/ kg), and the treatment group started vanadium treatment five days post diabetic induction and continued until being sacrificed at week 10. Using light and electron microscopy examinations, we observed in the model group substantial damage to the aorta tissue such as damaged endothelium, degenerative cellular changes with vacuolated cytoplasm and thickened internal elastic lamina that were substantially ameliorated by vanadium. Administration of vanadium to diabetic rats also significantly (p<0.05) reduced blood levels of glucose, hyperlipidemia and biomarkers of inflammation (TNF-a, IL-6). We conclude that vanadium protects against T2DM-induced aortic ultrastructural damage in rats, which is associated with the inhibition of blood sugar and lipid and inflammatory biomarkers.


El potencial efecto inhibidor del agente imitador de la insulina, el vanadio en las alteraciones inducidas por la diabetes mellitus tipo 2 (DM2) en la ultraestructura de la aorta, asociada con la supresión de dislipidemia y los biomarcadores de inflamación no se ha investigado anteriormente. El objetivo fue estudiar las propiedades del vanadio para proteger contra la lesión aórtica inducida a la DM2, a través de la inhibición de los lípidos sanguíneos y los biomarcadores inflamatorios. La DM2 fue inducida en ratas con una dieta alta en grasas y estreptozotocina (50 mg / kg), y el grupo de tratamiento fue sometido a un régimen continuo con vanadio, cinco días después de la inducción diabética hasta ser sacrificadas en la semana 10. Se utilizaron exámenes de luz y microscopía electrónica en el grupo modelo y se observó un daño sustancial al tejido de la aorta, como también en el endotelio; los cambios celulares degenerativos con citoplasma vacuolado y lámina elástica interna engrosada mejoró sustancialmente con vanadio. La administración de vanadio a ratas diabéticas también redujo significativamente (p <0,05) los niveles sanguíneos de la glucosa, hiperlipidemia y los biomarcadores de inflamación (TNFa, IL-6). En conclusión, el vanadio protege contra el daño ultraestructural aórtico inducido por T2DM en ratas, que es asociado con la inhibición del azúcar en la sangre y los biomarcadores de lípidos y de inflamatorios.


Assuntos
Animais , Masculino , Ratos , Aorta/efeitos dos fármacos , Vanádio/administração & dosagem , Diabetes Mellitus Tipo 2/complicações , Aorta/lesões , Aorta/ultraestrutura , Doenças da Aorta/etiologia , Vanádio/farmacologia , Ratos Sprague-Dawley , Microscopia Eletrônica de Transmissão , Modelos Animais de Doenças , Dislipidemias/tratamento farmacológico , Inflamação/tratamento farmacológico
17.
Ecotoxicol Environ Saf ; 193: 110318, 2020 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-32105945

RESUMO

The current study aimed to examine, for the first time, the relationship between exposure to deltamethrin (DLM) and atherogenic lipid profile disorders in adult Wistar rats, as well as, to verify the mechanism of the beneficial role of Zygophyllum album leaves extracts (ZALE). The experimental study was assessed using DLM (4 mg/kg b.w) either alone or co administered with ZALE (400 mg/kg b.w) orally for 90 days in rats. RP-HPLC-DAD-ESI-QTOF-MS was used to identify the bioactive metabolites present in ZALE. Plasmatic and aortic total cholesterol (TC), LDL-cholesterol (LDL-C), native LDL (LDL-apo B-100) and oxidized LDL (ox-LDL) were evaluated using auto-analyzer and a sandwich ELISA, respectively. The protein expressions of LDLR (native LDL receptor) and CD36 (Scavenger receptor class B) were evaluated in aorta or liver with a Western blot. The pathology has been confirmed with lipid stain (Oil Red O). Phytochemicals analysis revealed the presence of fifteen saponins in ZALE. Rats intoxicated with DLM revealed a significant increase in plasmatic and aortic lipid profile (TC, LDL-C, LDL-apo B-100 and ox-LDL), as well as, the concentration of the plasmatic cytokines include TNF-α, IL-2 and IL-6, compared to control. Hepatic native LDL and aortic CD36 receptor expression were increased in DLM treated group, however aortic LDL-R does not present any modification, when compared to control. The detected disturbances in lipid parameters were supported by Oil Red O applied. Due to their antioxidant activity, the bioactive compounds in ZALE as powerful agents able to prevent the pro-atherogenic effect observed in DLM-treated animals. These metabolites modulated most of inflammatory markers, prevented accumulation of lipid and lipoprotein biomarkers, regulated the major receptor regulators of hepatic cholesterol metabolism, as well as normalize lipid distribution in liver and aorta tissue.


Assuntos
Aorta/efeitos dos fármacos , Aterosclerose/prevenção & controle , Poluentes Ambientais/toxicidade , Lipoproteínas LDL/sangue , Nitrilos/toxicidade , Piretrinas/toxicidade , Saponinas/farmacologia , Zygophyllum/química , Animais , Aorta/imunologia , Aorta/metabolismo , Aterosclerose/imunologia , Aterosclerose/metabolismo , Antígenos CD36/metabolismo , Colesterol/metabolismo , Metabolismo dos Lipídeos/efeitos dos fármacos , Fígado/efeitos dos fármacos , Fígado/imunologia , Fígado/metabolismo , Masculino , Folhas de Planta/química , Ratos , Ratos Wistar , Receptores de LDL/metabolismo , Saponinas/isolamento & purificação , Fator de Necrose Tumoral alfa/metabolismo
18.
Int J Med Sci ; 17(1): 21-32, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31929735

RESUMO

This study examined the possible upstream cellular signaling pathway associated with nitric oxide (NO)-mediated inhibition of phenylephrine-induced contraction in isolated rat aortae in response to mild hypothermia, with a particular focus on endothelial Rho-kinase. We examined the effects of mild hypothermia (33°C), wortmannin, Nω-nitro-L-arginine methyl ester (L-NAME), Y-27632, 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ) and methylene blue, alone and combined, on phenylephrine-induced contraction in isolated rat aortae. Finally, we examined the effects of mild hypothermia, wortmannin, Y-27632 and L-NAME, alone and combined, on endothelial nitric oxide synthase (eNOS) and endothelial Rho-kinase membrane translocation induced by phenylephrine. Mild hypothermia attenuated phenylephrine-induced contraction only in endothelium-intact aortae. L-NAME, wortmannin, ODQ and methylene blue increased phenylephrine-induced contraction of endothelium-intact aortae pretreated at 33°C. Wortmannin did not significantly alter the L-NAME-induced enhancement of phenylephrine-induced maximal contraction of endothelium-intact aortae pretreated at 33°C. Wortmannin abolished the ability of Y-27632 to magnify the hypothermic inhibition of maximal phenylephrine-induced contraction. Wortmannin and L-NAME inhibited the enhancing effect of mild hypothermia on phenylephrine-induced eNOS phosphorylation. Y-27632 and L-NAME attenuated the enhancing effect of hypothermia on phenylephrine-induced endothelial Rho-kinase membrane translocation. The results suggest that hypothermia-induced, NO-dependent inhibition of phenylephrine-induced contraction is mediated by phosphoinositide 3-kinase and inhibited by endothelial Rho-kinase activation.


Assuntos
Aorta/metabolismo , Hipotermia Induzida/efeitos adversos , Óxido Nítrico/genética , Quinases Associadas a rho/genética , Amidas/farmacologia , Animais , Aorta/efeitos dos fármacos , Aorta/crescimento & desenvolvimento , Aorta/patologia , Endotélio Vascular/efeitos dos fármacos , Endotélio Vascular/metabolismo , Humanos , Contração Muscular/efeitos dos fármacos , Contração Muscular/genética , Músculo Liso Vascular/efeitos dos fármacos , Músculo Liso Vascular/metabolismo , Óxido Nítrico/metabolismo , Óxido Nítrico Sintase Tipo III/genética , Fenilefrina/farmacologia , Fosfatidilinositol 3-Quinases/genética , Fosforilação/efeitos dos fármacos , Piridinas/farmacologia , Ratos , Transdução de Sinais/efeitos dos fármacos , Vasoconstrição/genética
19.
Biomed Pharmacother ; 122: 109760, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31918287

RESUMO

AIMS: Siglec-E, the mouse ortholog of human Siglec-9, is an immunosuppressive cell surface receptor. Both Siglec-E and Siglec-9 are primarily found on neutrophils, macrophages, and monocytes. When Siglec-E binds to sialoglycan ligands in its extracellular environment, it halts the immune cells' inflammatory responses. In the present study, we aimed to investigate expression, mechanisms of action and regulation of Siglec-E ligands during vascular inflammation induced by E. coli lipopolysaccharides (LPS) in mouse aorta. METHODS: The distribution, molecular size and glycoprotein class of Siglec-E ligands on mouse aorta were determined, and the protein carrier of the ligands was identified. In vivo, the expression of Siglec-E ligands was detected after LPS treatment, with or without NF-κB inhibitor administration. In vitro, cultured primary mouse aortic endothelial cells (MAECs) were used to study changes in expression of Siglec-E ligands induced by LPS with or without NF-κB inhibitors. MAECs induced by LPS were co-cultured with macrophages and the effect of increased expression of Siglec-E ligands analyzed. RESULTS: Siglec-E ligands are O-linked sialoglycoproteins with molecular weights of 70-300 kDa and are distributed broadly on mouse aorta as well as on MAECs in vitro. In vivo, the expression of Siglec-E ligands was increased in mice aortas in response to LPS treatment in an NF-κB signaling pathway dependent manner. In MAECs, the expression of Siglec-E ligands was also increased by LPS via an NF-κB signaling pathway. Deleted in malignant brain tumors-1 was identified to be one of multiple protein carriers of Siglec-E ligands, and glycans of ligands involved in MAECs induced by LPS. Notably, co-incubation of macrophages with LPS-treated MAECs induced macrophage apoptosis and decreased macrophage phagocytosis, effects that were completely reversed by blocking Siglec-E binding to Siglec-E ligands. CONCLUSIONS: These data demonstrated that Siglec-E ligands were highly expressed in response to LPS-induced vascular inflammation and inhibited the immune response of macrophages, which may be a therapeutic strategy to interfere with vascular inflammation.


Assuntos
Antígenos CD/metabolismo , Antígenos de Diferenciação de Linfócitos B/metabolismo , Imunossupressores/farmacologia , Lipopolissacarídeos/farmacologia , NF-kappa B/metabolismo , Lectinas Semelhantes a Imunoglobulina de Ligação ao Ácido Siálico/metabolismo , Transdução de Sinais/efeitos dos fármacos , Regulação para Cima/efeitos dos fármacos , Animais , Aorta/efeitos dos fármacos , Aorta/metabolismo , Células Endoteliais/efeitos dos fármacos , Células Endoteliais/metabolismo , Escherichia coli/efeitos dos fármacos , Inflamação/tratamento farmacológico , Inflamação/metabolismo , Ligantes , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Camundongos , Camundongos Endogâmicos BALB C , Monócitos/efeitos dos fármacos , Monócitos/metabolismo , Transdução de Sinais/fisiologia , Ativação Transcricional/efeitos dos fármacos
20.
Artigo em Inglês | MEDLINE | ID: mdl-31922896

RESUMO

Proliferative diabetic retinopathy (PDR) is a progressive disease predominantly involving pathological angiogenesis and is characterized by the development of immature, fragile, and easily hemorrhagic new vessels. Advanced glycation end products (AGEs) and the receptor for AGEs (RAGE) play important roles in the progression of diabetic retinopathy. Our previous studies demonstrated that AGEs promoted HUVEC angiogenesis by inducing moesin phosphorylation via RhoA/Rho-associated protein kinase (ROCK) pathway. The aim of this study was to further confirm AGE-induced angiogenesis in vivo and the involvement of RAGE, ROCK, and moesin phosphorylation in this process. We performed the study in an AGE-treated mouse model with various angiogenesis assays in multiple in vivo and ex vivo models. The results demonstrated that AGEs promoted significant neovascularization in whole mount retina and mouse aortic ring of adult and postnatal mice and in Matrigel plug as well, which were consistently accompanied by increased moesin phosphorylation. The increase of AGE-evoked neovascularization and moesin phosphorylation were both attenuated by RAGE knockout or ROCK inhibitor Y27632 administration in mice. We also revealed the pathological characteristics of AGE-promoted angiogenesis by demonstrating the decrease of pericyte coverage and the disarranged endothelial alignment in microvessels. In conclusion, this study provides in vivo evidences that AGEs induce immature angiogenesis by binding to RAGE, activating the RhoA/ROCK signal pathway and inducing moesin phosphorylation.NEW & NOTEWORTHY Advanced glycation end product (AGE)-induced formation of neovessels and phosphorylation of moesin in retina and aortic ring required AGE receptors. AGEs increased neovessels and the phosphorylation of moesin in retina and aortic ring via RhoA/ROCK pathway. AGE-induced immature angiogenesis in AGE-treated mouse retina and aortic ring. The AGE-RAGE axis and moesin could be candidate targets for overcoming relative diseases.


Assuntos
Produtos Finais de Glicação Avançada/farmacologia , Neovascularização Patológica/metabolismo , Retina/efeitos dos fármacos , Neovascularização Retiniana/metabolismo , Amidas/farmacologia , Animais , Aorta/efeitos dos fármacos , Aorta/metabolismo , Permeabilidade Capilar/efeitos dos fármacos , Camundongos , Camundongos Knockout , Proteínas dos Microfilamentos/metabolismo , Fosforilação/efeitos dos fármacos , Piridinas/farmacologia , Receptor para Produtos Finais de Glicação Avançada/genética , Receptor para Produtos Finais de Glicação Avançada/metabolismo , Retina/metabolismo , Transdução de Sinais/efeitos dos fármacos
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