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1.
Int J Mol Sci ; 22(12)2021 Jun 18.
Artigo em Inglês | MEDLINE | ID: mdl-34207234

RESUMO

Filamin A (FLNA) is a large actin-binding cytoskeletal protein that is important for cell motility by stabilizing actin networks and integrating them with cell membranes. Interestingly, a C-terminal fragment of FLNA can be cleaved off by calpain to stimulate adaptive angiogenesis by transporting multiple transcription factors into the nucleus. Recently, increasing evidence suggests that FLNA participates in the pathogenesis of cardiovascular and respiratory diseases, in which the interaction of FLNA with transcription factors and/or cell signaling molecules dictate the function of vascular cells. Localized FLNA mutations associate with cardiovascular malformations in humans. A lack of FLNA in experimental animal models disrupts cell migration during embryogenesis and causes anomalies, including heart and vessels, similar to human malformations. More recently, it was shown that FLNA mediates the progression of myocardial infarction and atherosclerosis. Thus, these latest findings identify FLNA as an important novel mediator of cardiovascular development and remodeling, and thus a potential target for therapy. In this update, we summarized the literature on filamin biology with regard to cardiovascular cell function.


Assuntos
Doenças Cardiovasculares/genética , Filaminas/genética , Animais , Doenças Cardiovasculares/metabolismo , Doenças Cardiovasculares/patologia , Endotélio Vascular/metabolismo , Endotélio Vascular/patologia , Filaminas/metabolismo , Humanos , Músculo Liso Vascular/metabolismo , Músculo Liso Vascular/patologia , Miócitos Cardíacos/metabolismo , Miócitos Cardíacos/patologia
2.
Molecules ; 26(12)2021 Jun 10.
Artigo em Inglês | MEDLINE | ID: mdl-34200914

RESUMO

Flavonoids are a group of secondary metabolites derived from plant-based foods, and they offer many health benefits in different stages of several diseases. This review will focus on their effects on ion channels expressed in vascular smooth muscle during atherosclerosis. Since ion channels can be regulated by redox potential, it is expected that during the onset of oxidative stress-related diseases, ion channels present changes in their conductive activity, impacting the progression of the disease. A typical oxidative stress-related condition is atherosclerosis, which involves the dysfunction of vascular smooth muscle. We aim to present the state of the art on how redox potential affects vascular smooth muscle ion channel function and summarize if the benefits observed in this disease by using flavonoids involve restoring the ion channel activity.


Assuntos
Aterosclerose/tratamento farmacológico , Flavonoides/farmacologia , Músculo Liso Vascular/efeitos dos fármacos , Animais , Aterosclerose/metabolismo , Progressão da Doença , Humanos , Canais Iônicos/metabolismo , Músculo Liso Vascular/metabolismo , Miócitos de Músculo Liso/efeitos dos fármacos , Miócitos de Músculo Liso/metabolismo , Oxirredução/efeitos dos fármacos
3.
Int J Mol Sci ; 22(10)2021 May 12.
Artigo em Inglês | MEDLINE | ID: mdl-34066088

RESUMO

Familial hypercholesterolemia (FH) is increasingly associated with inflammation, a phenotype that persists despite treatment with lipid lowering therapies. The alternative C3 complement system (C3), as a key inflammatory mediator, seems to be involved in the atherosclerotic process; however, the relationship between C3 and lipids during plaque progression remains unknown. The aim of the study was to investigate by a systems biology approach the role of C3 in relation to lipoprotein levels during atherosclerosis (AT) progression and to gain a better understanding on the effects of C3 products on the phenotype and function of human lipid-loaded vascular smooth muscle cells (VSMCs). By mass spectrometry and differential proteomics, we found the extracellular matrix (ECM) of human aortas to be enriched in active components of the C3 complement system, with a significantly different proteomic signature in AT segments. Thus, C3 products were more abundant in AT-ECM than in macroscopically normal segments. Furthermore, circulating C3 levels were significantly elevated in FH patients with subclinical coronary AT, evidenced by computed tomographic angiography. However, no correlation was identified between circulating C3 levels and the increase in plaque burden, indicating a local regulation of the C3 in AT arteries. In cell culture studies of human VSMCs, we evidenced the expression of C3, C3aR (anaphylatoxin receptor) and the integrin αMß2 receptor for C3b/iC3b (RT-PCR and Western blot). C3mRNA was up-regulated in lipid-loaded human VSMCs, and C3 protein significantly increased in cell culture supernatants, indicating that the C3 products in the AT-ECM have a local vessel-wall niche. Interestingly, C3a and iC3b (C3 active fragments) have functional effects on VSMCs, significantly reversing the inhibition of VSMC migration induced by aggregated LDL and stimulating cell spreading, organization of F-actin stress fibers and attachment during the adhesion of lipid-loaded human VSMCs. This study, by using a systems biology approach, identified molecular processes involving the C3 complement system in vascular remodeling and in the progression of advanced human atherosclerotic lesions.


Assuntos
Aterosclerose/patologia , Complemento C3/metabolismo , Hiperlipoproteinemia Tipo II/patologia , Músculo Liso Vascular/patologia , Miócitos de Músculo Liso/patologia , Proteoma/metabolismo , Adulto , Aterosclerose/imunologia , Aterosclerose/metabolismo , Estudos de Casos e Controles , Adesão Celular , Células Cultivadas , Feminino , Humanos , Hiperlipoproteinemia Tipo II/imunologia , Hiperlipoproteinemia Tipo II/metabolismo , Masculino , Pessoa de Meia-Idade , Músculo Liso Vascular/imunologia , Músculo Liso Vascular/metabolismo , Miócitos de Músculo Liso/imunologia , Miócitos de Músculo Liso/metabolismo , Proteoma/análise , Remodelação Vascular , Cicatrização , Adulto Jovem
4.
Int J Mol Sci ; 22(11)2021 May 21.
Artigo em Inglês | MEDLINE | ID: mdl-34064290

RESUMO

Inositol 1,4,5-triphosphate receptor-associated cGMP kinase substrate 1 (IRAG1) is a substrate protein of the NO/cGMP-signaling pathway and forms a ternary complex with the cGMP-dependent protein kinase Iß (PKGIß) and the inositol triphosphate receptor I (IP3R-I). Functional studies about IRAG1 exhibited that IRAG1 is specifically phosphorylated by the PKGIß, regulating cGMP-mediated IP3-dependent Ca2+-release. IRAG1 is widely distributed in murine tissues, e.g., in large amounts in smooth muscle-containing tissues and platelets, but also in lower amounts, e.g., in the spleen. The NO/cGMP/PKGI signaling pathway is important in several organ systems. A loss of PKGI causes gastrointestinal disorders, anemia and splenomegaly. Due to the similar tissue distribution of the PKGIß to IRAG1, we investigated the pathophysiological functions of IRAG1 in this context. Global IRAG1-KO mice developed gastrointestinal bleeding, anemia-associated splenomegaly and iron deficiency. Additionally, Irag1-deficiency altered the protein levels of some cGMP/PKGI signaling proteins-particularly a strong decrease in the PKGIß-in the colon, spleen and stomach but did not change mRNA-expression of the corresponding genes. The present work showed that a loss of IRAG1 and the PKGIß/IRAG1 signaling has a crucial function in the development of gastrointestinal disorders and anemia-associated splenomegaly. Furthermore, global Irag1-deficient mice are possible in vivo model to investigate PKGIß protein functions.


Assuntos
Anemia/metabolismo , Proteína Quinase Dependente de GMP Cíclico Tipo I/metabolismo , Transdução de Sinais/fisiologia , Esplenomegalia/metabolismo , Animais , Cálcio/metabolismo , Colo/metabolismo , GMP Cíclico/metabolismo , Feminino , Receptores de Inositol 1,4,5-Trifosfato/metabolismo , Masculino , Camundongos , Camundongos Knockout , Músculo Liso Vascular/metabolismo , Fosforilação/fisiologia , RNA Mensageiro/metabolismo , Baço/metabolismo , Estômago
5.
Int J Mol Sci ; 22(11)2021 May 25.
Artigo em Inglês | MEDLINE | ID: mdl-34070527

RESUMO

Excessive proliferation and migration of vascular smooth muscle cells (VSMCs) contribute to the development of atherosclerosis and restenosis. Glycolysis and glutaminolysis are increased in rapidly proliferating VSMCs to support their increased energy requirements and biomass production. Thus, it is essential to develop new pharmacological tools that regulate metabolic reprogramming in VSMCs for treatment of atherosclerosis. The effects of 6-diazo-5-oxo-L-norleucine (DON), a glutamine antagonist, have been broadly investigated in highly proliferative cells; however, it is unclear whether DON inhibits proliferation of VSMCs and neointima formation. Here, we investigated the effects of DON on neointima formation in vivo as well as proliferation and migration of VSMCs in vitro. DON simultaneously inhibited FBS- or PDGF-stimulated glycolysis and glutaminolysis as well as mammalian target of rapamycin complex I activity in growth factor-stimulated VSMCs, and thereby suppressed their proliferation and migration. Furthermore, a DON-derived prodrug, named JHU-083, significantly attenuated carotid artery ligation-induced neointima formation in mice. Our results suggest that treatment with a glutamine antagonist is a promising approach to prevent progression of atherosclerosis and restenosis.


Assuntos
Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Diazo-Oxo-Norleucina/farmacologia , Glutamina/antagonistas & inibidores , Glicólise/efeitos dos fármacos , Músculo Liso Vascular/efeitos dos fármacos , Neointima/tratamento farmacológico , Fosforilação Oxidativa/efeitos dos fármacos , Animais , Antimetabólitos Antineoplásicos/farmacologia , Ciclo Celular/efeitos dos fármacos , Células Cultivadas , Diazo-Oxo-Norleucina/análogos & derivados , Glutamina/metabolismo , Imuno-Histoquímica , Masculino , Alvo Mecanístico do Complexo 1 de Rapamicina/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Músculo Liso Vascular/metabolismo , Neointima/metabolismo , Fator de Crescimento Derivado de Plaquetas/farmacologia , Ratos , Ratos Sprague-Dawley , Soroalbumina Bovina/farmacologia
6.
Int J Mol Sci ; 22(11)2021 May 21.
Artigo em Inglês | MEDLINE | ID: mdl-34063769

RESUMO

Maturation of the cardiovascular system is associated with crucial structural and functional remodeling. Thickening of the arterial wall, maturation of the sympathetic innervation, and switching of the mechanisms of arterial contraction from calcium-independent to calcium-dependent occur during postnatal development. All these processes promote an almost doubling of blood pressure from the moment of birth to reaching adulthood. This review focuses on the developmental alterations of potassium channels functioning as key smooth muscle membrane potential determinants and, consequently, vascular tone regulators. We present evidence that the pattern of potassium channel contribution to vascular control changes from Kir2, Kv1, Kv7 and TASK-1 channels to BKCa channels with maturation. The differences in the contribution of potassium channels to vasomotor tone at different stages of postnatal life should be considered in treatment strategies of cardiovascular diseases associated with potassium channel malfunction.


Assuntos
Artérias/metabolismo , Miócitos de Músculo Liso/metabolismo , Canais de Potássio/metabolismo , Animais , Pressão Sanguínea/fisiologia , Cálcio/metabolismo , Potenciais da Membrana/fisiologia , Músculo Liso Vascular/metabolismo , Cuidado Pós-Natal/métodos
7.
Oxid Med Cell Longev ; 2021: 6644970, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33968296

RESUMO

Vascular smooth muscle cell (VSMC) phenotypic modulation plays an important role in the occurrence and development of in-stent restenosis (ISR), the underlying mechanism of which remains a key issue needing to be urgently addressed. This study is designed to investigate the role of plasma small extracellular vesicles (sEV) in VSMC phenotypic modulation. sEV were isolated from the plasma of patients with ISR (ISR-sEV) or not (Ctl-sEV) 1 year after coronary stent implantation using differential ultracentrifugation. Plasma sEV in ISR patients are elevated markedly and decrease the expression of VSMC contractile markers α-SMA and calponin and increase VSMC proliferation. miRNA sequencing and qRT-PCR validation identified that miRNA-501-5p was the highest expressed miRNA in the plasma ISR-sEV compared with Ctl-sEV. Then, we found that sEV-carried miRNA-501-5p level was significantly higher in ISR patients, and the level of plasma sEV-carried miRNA-501-5p linearly correlated with the degree of restenosis (R 2 = 0.62). Moreover, miRNA-501-5p inhibition significantly increased the expression of VSMC contractile markers α-SMA and calponin and suppressed VSMC proliferation and migration; in vivo inhibition of miRNA-501-5p could also blunt carotid artery balloon injury induced VSMC phenotypic modulation in rats. Mechanically, miRNA-501-5p promoted plasma sEV-induced VSMC proliferation by targeting Smad3. Notably, endothelial cells might be the major origins of miRNA-501-5p. Collectively, these findings showed that plasma sEV-carried miRNA-501-5p promotes VSMC phenotypic modulation-mediated ISR through targeting Smad3.


Assuntos
Reestenose Coronária/metabolismo , Vesículas Extracelulares/metabolismo , MicroRNAs/metabolismo , Músculo Liso Vascular/metabolismo , Animais , Humanos , Masculino , Fenótipo , Ratos , Ratos Sprague-Dawley
8.
Toxins (Basel) ; 13(4)2021 04 20.
Artigo em Inglês | MEDLINE | ID: mdl-33924041

RESUMO

Ergotism is a common and increasing problem in Saskatchewan's livestock. Chronic exposure to low concentrations of ergot alkaloids is known to cause severe arterial vasoconstriction and gangrene through the activation of adrenergic and serotonergic receptors on vascular smooth muscles. The acute vascular effects of a single oral dose with high-level exposure to ergot alkaloids remain unknown and are examined in this study. This study had two main objectives; the first was to evaluate the role of α1-adrenergic receptors in mediating the acute vasocontractile response after single-dose exposure in sheep. The second was to examine whether terazosin (TE) could abolish the vascular contractile effects of ergot alkaloids. Twelve adult female sheep were randomly placed into control and exposure groups (n = 6/group). Ergot sclerotia were collected and finely ground. The concentrations of six ergot alkaloids (ergocornine, ergocristine, ergocryptine, ergometrine, ergosine, and ergotamine) were determined using HPLC/MS at Prairie Diagnostic Services Inc., (Saskatoon, SK, Canada). Each ewe within the treatment group received a single oral treatment of ground ergot sclerotia at a dose of 600 µg/kg BW (total ergot) while each ewe in the control group received water. Animals were euthanized 12 h after the treatment, and the pedal artery (dorsal metatarsal III artery) from the left hind limb from each animal was carefully dissected and mounted in an isolated tissue bath. The vascular contractile response to phenylephrine (PE) (α1-adrenergic agonist) was compared between the two groups before and after TE (α1-adrenergic antagonist) treatment. Acute exposure to ergot alkaloids resulted in a 38% increase in vascular sensitivity to PE compared to control (Ctl EC50 = 1.74 × 10-6 M; Exp EC50 = 1.079 × 10-6 M, p = 0.046). TE treatment resulted in a significant dose-dependent increase in EC50 in both exposure and control groups (p < 0.05 for all treatments). Surprisingly, TE effect was significantly more pronounced in the ergot exposed group compared to the control group at two of the three concentrations of TE (TE 30 nM, p = 0.36; TE 100 nM, p < 0.001; TE 300 nM, p < 0.001). Similar to chronic exposure, acute exposure to ergot alkaloids results in increased vascular sensitivity to PE. TE is a more potent dose-dependent antagonist for the PE contractile response in sheep exposed to ergot compared to the control group. This study may indicate that the dry gangrene seen in sheep, and likely other species, might be related to the activation of α1-adrenergic receptor. This effect may be reversed using TE, especially at early stages of the disease before cell death occurs. This study may also indicate that acute-single dose exposure scenario may be useful in the study of vascular effects of ergot alkaloids.


Assuntos
Alcaloides de Claviceps/toxicidade , Ergotismo/fisiopatologia , Membro Posterior/irrigação sanguínea , Músculo Liso Vascular/efeitos dos fármacos , Receptores Adrenérgicos alfa 1/metabolismo , Vasoconstrição/efeitos dos fármacos , Vasoconstritores/farmacologia , Antagonistas de Receptores Adrenérgicos alfa 1/farmacologia , Animais , Artérias/efeitos dos fármacos , Artérias/metabolismo , Ergotismo/metabolismo , Ergotismo/prevenção & controle , Feminino , Músculo Liso Vascular/metabolismo , Prazosina/análogos & derivados , Prazosina/farmacologia , Carneiro Doméstico , Transdução de Sinais
9.
Oxid Med Cell Longev ; 2021: 5564884, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33859778

RESUMO

Vascular smooth muscle cell (VSMC) apoptosis is a major defining feature of abdominal aortic aneurysm (AAA) and mainly caused by inflammatory cell infiltration. Smooth muscle (SM) 22α prevents AAA formation through suppressing NF-κB activation. However, the role of SM22α in VSMC apoptosis is controversial. Here, we identified that SM22α loss contributed to apoptosis of VSMCs via activation of macrophages. Firstly, deficiency of SM22α enhanced the interaction of VSMCs with macrophages. Macrophages were retained and activated by Sm22α -/- VSMCs via upregulating VCAM-1 expression. The ratio of apoptosis was increased by 1.62-fold in VSMCs treated with the conditional media (CM) from activated RAW264.7 cells, compared to that of the control CM (P < 0.01), and apoptosis of Sm22α -/- VSMCs was higher than that of WT VSMCs (P < 0.001). Next, circRasGEF1B from activated macrophages was delivered into VSMCs promoting ZFP36 expression via stabilization of ZFP36 mRNA. Importantly, circRasGEF1B, as a scaffold, guided ZFP36 to preferentially bind to and decay Bcl-2 mRNA in a sequence-specific manner and triggered apoptosis of VSMCs, especially in Sm22α -/- VSMCs. These findings reveal a novel mechanism by which the circRasGEF1B-ZFP36 axis mediates macrophage-induced VSMC apoptosis via decay of Bcl-2 mRNA, whereas Sm22α -/- VSMCs have a higher sensitivity to apoptosis.


Assuntos
Macrófagos/citologia , Macrófagos/metabolismo , Proteínas dos Microfilamentos/deficiência , Proteínas Musculares/deficiência , Músculo Liso Vascular/citologia , Músculo Liso Vascular/metabolismo , RNA Circular/metabolismo , Animais , Apoptose/fisiologia , Comunicação Celular/fisiologia , Técnicas de Reprogramação Celular , Humanos , Masculino , Camundongos , Proteínas dos Microfilamentos/genética , Proteínas dos Microfilamentos/metabolismo , Proteínas Musculares/genética , Proteínas Musculares/metabolismo , Células RAW 264.7 , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Transdução de Sinais , Tristetraprolina/biossíntese , Tristetraprolina/genética , Tristetraprolina/metabolismo
10.
Ann R Coll Surg Engl ; 103(6): 452-458, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-33851890

RESUMO

INTRODUCTION: Several treatment modalities have been postulated to improve the efficacy of varicose vein treatment. Addition of glycerine to the sclerosing material has been documented to increase its viscosity and subsequently prolong the duration of stability, in addition to the direct sclerosing effect of glycerine. This histological and immunohistochemical study investigated the efficacy of addition of glycerine 72% to sclerotherapy on the human varicose vein. METHODS: After surgical stripping of great saphenous veins, three equal segments were resected between two clamps. Specimen 1 was injected with saline only, specimen 2 was exposed to foam sclerosant 2%, and specimen 3 was exposed to a mixture of foam sclerosant 2% and glycerine 72%. All segments were left for 5min. Vein segments were then processed for histological and immunohistochemical study. RESULTS: Microscopically, haematoxylin and eosin-stained specimen 1 showed endothelial swelling, cytoplasmic eosinophilia and pyknotic nuclei. The media showed sarcoplasm vacuolisation and necrosis. Specimen 3 showed hypereosinophilic sarcoplasm of the smooth muscle fibres. Oedema was less evident, with a relative decrease in the thickness of the wall compared with specimen 2. Immunohistochemically, the expression of smooth muscle actin was weak in specimen 3 compared with specimens 1 and 2. Expression of CD31 antibody was much reduced in specimen 2 which showed conserved islands of endothelial cells. By contrast, there was a complete loss of endothelial cells in specimen 3. CONCLUSION: Addition of glycerine 72% to foam sclerosant has a more damaging effect on human vein wall.


Assuntos
Edema/patologia , Glicerol/farmacologia , Polidocanol/farmacologia , Veia Safena/patologia , Soluções Esclerosantes/farmacologia , Actinas/metabolismo , Combinação de Medicamentos , Endotélio/efeitos dos fármacos , Endotélio/metabolismo , Endotélio/patologia , Glicerol/uso terapêutico , Humanos , Imuno-Histoquímica , Músculo Liso Vascular/efeitos dos fármacos , Músculo Liso Vascular/metabolismo , Músculo Liso Vascular/patologia , Molécula-1 de Adesão Celular Endotelial a Plaquetas/metabolismo , Polidocanol/uso terapêutico , Veia Safena/efeitos dos fármacos , Veia Safena/metabolismo , Soluções Esclerosantes/uso terapêutico , Varizes/terapia , Viscosidade
11.
Toxicol Appl Pharmacol ; 421: 115543, 2021 06 15.
Artigo em Inglês | MEDLINE | ID: mdl-33872679

RESUMO

Nimodipine is a clinically used dihydropyridine L-type calcium channel antagonist that effectively inhibits transmembrane Ca2+ influx following the depolarization of smooth muscle cells, but the detailed effect on smooth muscle contraction is not fully understood. Ca2+-activated Cl- channels (CaCCs) in vascular smooth muscle cells (VSMCs) may regulate vascular contractility. We found that nimodipine can inhibit transmembrane protein 16A (TMEM16A) activity in a concentration-dependent manner by cell-based fluorescence-quenching assay and short-circuit current analysis, with an IC50 value of ~5 µM. Short-circuit current analysis also showed that nimodipine prevented Ca2+-activated Cl- current in both HT-29 cells and mouse colonic epithelia accompanied by significantly decreased cytoplasmic Ca2+ concentrations. In the absence of extracellular Ca2+, nimodipine still exhibited an inhibitory effect on TMEM16A/CaCCs. Additionally, the application of nimodipine to CFTR-expressing FRT cells and mouse colonic mucosa resulted in mild activation of CFTR-mediated Cl- currents. Nimodipine inhibited basolateral CCh-activated K+ channel activity with no effect on Na+/K+-ATPase activity. Evaluation of intestinal smooth muscle contraction showed that nimodipine inhibits intestinal smooth muscle contractility and frequency, with an activity pattern that was similar to that of non-specific inhibitors of CaCCs. In aortic smooth muscle, the expression of TMEM16A in thoracic aorta is higher than that in abdominal aorta, corresponding to stronger maximum contractility in thoracic aorta smooth muscle stimulated by phenylephrine (PE) and Eact. Nimodipine completely inhibited the contraction of aortic smooth muscle stimulated by Eact, and partially inhibited the contraction stimulated by PE. In summary, the results indicate that nimodipine effectively inhibits TMEM16A/CaCCs by reduction transmembrane Ca2+ influx and directly interacting with TMEM16A, explaining the mechanisms of nimodipine relaxation of intestinal and aortic smooth muscle contraction and providing new targets for pharmacological applications.


Assuntos
Anoctamina-1/antagonistas & inibidores , Bloqueadores dos Canais de Cálcio/toxicidade , Contração Muscular/efeitos dos fármacos , Músculo Liso Vascular/metabolismo , Músculo Liso/efeitos dos fármacos , Nimodipina/toxicidade , Vasoconstrição/efeitos dos fármacos , Animais , Anoctamina-1/metabolismo , Aorta Abdominal/efeitos dos fármacos , Aorta Abdominal/metabolismo , Aorta Torácica/efeitos dos fármacos , Aorta Torácica/metabolismo , Sinalização do Cálcio/efeitos dos fármacos , Células HT29 , Humanos , Íleo/efeitos dos fármacos , Íleo/metabolismo , Técnicas In Vitro , Masculino , Camundongos Endogâmicos C57BL , Músculo Liso/metabolismo , Músculo Liso Vascular/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley
12.
Clin Chim Acta ; 519: 101-110, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-33887264

RESUMO

Vascular calcification (VC), which is closely associated with significant mortality in cardiovascular disease, chronic kidney disease (CKD), and/or diabetes mellitus, is characterized by abnormal deposits of hydroxyapatite minerals in the arterial wall. The impact of oxidative stress (OS) on the onset and progression of VC has not been well described. Nicotinamide adenine dinucleotide phosphate (NADPH) oxidases, xanthine oxidases, myeloperoxidase (MPO), nitric oxide synthases (NOSs), superoxide dismutase (SOD) and paraoxonases (PONs) are relevant factors that influence the production of reactive oxygen species (ROS). Furthermore, excess ROS-induced OS has emerged as a critical mediator promoting VC through several mechanisms, including phosphate balance, differentiation of vascular smooth muscle cells (VSMCs), inflammation, DNA damage, and extracellular matrix remodeling. Because OS is a significant regulator of VC, antioxidants may be considered as novel treatment options.


Assuntos
Músculo Liso Vascular , Calcificação Vascular , Humanos , Músculo Liso Vascular/metabolismo , Miócitos de Músculo Liso , NADPH Oxidases , Estresse Oxidativo , Espécies Reativas de Oxigênio/metabolismo , Calcificação Vascular/metabolismo
13.
Nutr Metab Cardiovasc Dis ; 31(5): 1635-1644, 2021 05 06.
Artigo em Inglês | MEDLINE | ID: mdl-33812737

RESUMO

BACKGROUND AND AIM: Our previous study found carotid baroreceptor stimulation (CBS) reduces body weight and white adipose tissue (WAT) weight, restores abnormal secretion of adipocytokines and inflammation factors, decreases systolic blood pressure (SBP) by inhibiting activation of sympathetic nervous system (SNS) and renin-angiotensin system (RAS) in obese rats. In this study, we explore effects of CBS on aortic remodeling in obese rats. METHODS AND RESULTS: Rats were fed high-fat diet (HFD) for 16 weeks to induce obesity and underwent either CBS device implantation and stimulation or sham operation at 8 weeks. BP and body weight were measured weekly. RAS activity of WAT, histological, biochemical and functional profiles of aortas were detected after 16 weeks. CBS effectively decreased BP in obese rats, downregulated mRNA expression of angiotensinogen (AGT) and renin in WAT, concentrations of AGT, renin, angiotensin II (Ang II), protein levels of Ang II receptor 1 (AT1R) and Ang II receptor 2 (AT2R) in WAT were declined. CBS inhibited reactive oxygen species (ROS) generation, inflammatory response and endoplasmic reticulum (ER) stress in aortas of obese rats, restrained vascular wall thickening and vascular smooth muscle cells (VSMCs) phenotypic switching, increased nitric oxide (NO) synthesis, promoted endothelium-dependent vasodilatation by decreasing protein expression of AT1R and leptin receptor (LepR), increasing protein expression of adiponectin receptor 1 (AdipoR1) in aortic VSMCs. CONCLUSION: CBS reduced BP and reversed aortic remodeling in obese rats, the underlying mechanism might be related to the suppressed SNS activity, restored adipocytokine secretion and restrained RAS activity of WAT.


Assuntos
Tecido Adiposo Branco/metabolismo , Terapia por Estimulação Elétrica , Músculo Liso Vascular/patologia , Obesidade/terapia , Pressorreceptores/fisiopatologia , Sistema Renina-Angiotensina , Remodelação Vascular , Adipocinas/metabolismo , Animais , Aorta Torácica/metabolismo , Aorta Torácica/patologia , Aorta Torácica/fisiopatologia , Pressão Arterial , Modelos Animais de Doenças , Terapia por Estimulação Elétrica/instrumentação , Células Endoteliais/metabolismo , Células Endoteliais/patologia , Neuroestimuladores Implantáveis , Masculino , Músculo Liso Vascular/metabolismo , Músculo Liso Vascular/fisiopatologia , Miócitos de Músculo Liso/metabolismo , Miócitos de Músculo Liso/patologia , Obesidade/metabolismo , Obesidade/patologia , Obesidade/fisiopatologia , Ratos Sprague-Dawley , Receptor Tipo 1 de Angiotensina/metabolismo , Receptores de Adiponectina , Receptores para Leptina/metabolismo , Vasodilatação
14.
Molecules ; 26(8)2021 Apr 16.
Artigo em Inglês | MEDLINE | ID: mdl-33923651

RESUMO

Curcumin is a natural compound that has been widely used as a food additive and medicine in Asian countries. Over several decades, diverse biological effects of curcumin have been elucidated, such as anti-inflammatory and anti-oxidative activities. Monocyte chemoattractant protein-1 (MCP-1) is a key inflammatory marker during the development of atherosclerosis, and curcumin blocks MCP-1 expression stimulated by various ligands. Hence, we studied the action of curcumin on lysophosphatidic acid (LPA) mediated MCP-1 expression and explored the specific underlying mechanisms. In human vascular smooth muscle cells, LPA induces Rho-associated protein kinase (ROCK) dependent transforming growth factor receptor (TGFBR1) transactivation, leading to glycosaminoglycan chain elongation. We found that LPA also signals via the TGFBR1 transactivation pathway to regulate MCP-1 expression. Curcumin blocks LPA mediated TGFBR1 transactivation and subsequent MCP-1 expression by blocking the ROCK signalling. In the vasculature, ROCK signalling regulates smooth muscle cell contraction, inflammatory cell recruitment, endothelial dysfunction and vascular remodelling. Therefore, curcumin as a ROCK signalling inhibitor has the potential to prevent atherogenesis via multiple ways.


Assuntos
Quimiocina CCL2/metabolismo , Curcumina/farmacologia , Lisofosfolipídeos/farmacologia , Quinases Associadas a rho/metabolismo , Animais , Western Blotting , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Humanos , Inflamação/metabolismo , Músculo Liso Vascular/efeitos dos fármacos , Músculo Liso Vascular/metabolismo , Receptores de Fatores de Crescimento Transformadores beta/metabolismo , Transdução de Sinais/efeitos dos fármacos
15.
Int J Mol Sci ; 22(6)2021 Mar 13.
Artigo em Inglês | MEDLINE | ID: mdl-33805714

RESUMO

Trifluoperazine (TFP), an antipsychotic drug approved by the Food and Drug Administration, has been show to exhibit anti-cancer effects. Pulmonary arterial hypertension (PAH) is a devastating disease characterized by a progressive obliteration of small pulmonary arteries (PAs) due to exaggerated proliferation and resistance to apoptosis of PA smooth muscle cells (PASMCs). However, the therapeutic potential of TFP for correcting the cancer-like phenotype of PAH-PASMCs and improving PAH in animal models remains unknown. PASMCs isolated from PAH patients were exposed to different concentrations of TFP before assessments of cell proliferation and apoptosis. The in vivo therapeutic potential of TFP was tested in two preclinical models with established PAH, namely the monocrotaline and sugen/hypoxia-induced rat models. Assessments of hemodynamics by right heart catheterization and histopathology were conducted. TFP showed strong anti-survival and anti-proliferative effects on cultured PAH-PASMCs. Exposure to TFP was associated with downregulation of AKT activity and nuclear translocation of forkhead box protein O3 (FOXO3). In both preclinical models, TFP significantly lowered the right ventricular systolic pressure and total pulmonary resistance and improved cardiac function. Consistently, TFP reduced the medial wall thickness of distal PAs. Overall, our data indicate that TFP could have beneficial effects in PAH and support the view that seeking new uses for old drugs may represent a fruitful approach.


Assuntos
Fármacos Cardiovasculares/farmacologia , Regulação da Expressão Gênica/efeitos dos fármacos , Hipertensão Pulmonar/tratamento farmacológico , Hipóxia/prevenção & controle , Miócitos de Músculo Liso/efeitos dos fármacos , Trifluoperazina/farmacologia , Animais , Antipsicóticos/farmacologia , Proliferação de Células/efeitos dos fármacos , Modelos Animais de Doenças , Avaliação Pré-Clínica de Medicamentos , Reposicionamento de Medicamentos , Feminino , Proteína Forkhead Box O3/genética , Proteína Forkhead Box O3/metabolismo , Hemodinâmica/efeitos dos fármacos , Humanos , Hipertensão Pulmonar/induzido quimicamente , Hipertensão Pulmonar/genética , Hipertensão Pulmonar/fisiopatologia , Hipóxia/induzido quimicamente , Hipóxia/genética , Hipóxia/fisiopatologia , Indóis/administração & dosagem , Monocrotalina/administração & dosagem , Músculo Liso Vascular/citologia , Músculo Liso Vascular/efeitos dos fármacos , Músculo Liso Vascular/metabolismo , Miócitos de Músculo Liso/citologia , Miócitos de Músculo Liso/metabolismo , Cultura Primária de Células , Proteínas Proto-Oncogênicas c-akt/genética , Proteínas Proto-Oncogênicas c-akt/metabolismo , Artéria Pulmonar/citologia , Artéria Pulmonar/efeitos dos fármacos , Artéria Pulmonar/metabolismo , Pirróis/administração & dosagem , Ratos , Ratos Sprague-Dawley , Survivina/genética , Survivina/metabolismo
16.
Int J Mol Sci ; 22(6)2021 Mar 14.
Artigo em Inglês | MEDLINE | ID: mdl-33799449

RESUMO

(1) Background: Tissue non-specific alkaline phosphatase (TNAP) is suspected to induce atherosclerosis plaque calcification. TNAP, during physiological mineralization, hydrolyzes the mineralization inhibitor inorganic pyrophosphate (PPi). Since atherosclerosis plaques are characterized by the presence of necrotic cells that probably release supraphysiological concentrations of ATP, we explored whether this extracellular adenosine triphosphate (ATP) is hydrolyzed into the mineralization inhibitor PPi or the mineralization stimulator inorganic phosphate (Pi), and whether TNAP is involved. (2) Methods: Murine aortic smooth muscle cell line (MOVAS cells) were transdifferentiated into chondrocyte-like cells in calcifying medium, containing ascorbic acid and ß-glycerophosphate. ATP hydrolysis rates were determined in extracellular medium extracted from MOVAS cultures during their transdifferentiation, using 31P-NMR and IR spectroscopy. (3) Results: ATP and PPi hydrolysis by MOVAS cells increased during transdifferentiation. ATP hydrolysis was sequential, yielding adenosine diphosphate (ADP), adenosine monophosphate (AMP), and adenosine without any detectable PPi. The addition of levamisole partially inhibited ATP hydrolysis, indicating that TNAP and other types of ectonucleoside triphoshatediphosphohydrolases contributed to ATP hydrolysis. (4) Conclusions: Our findings suggest that high ATP levels released by cells in proximity to vascular smooth muscle cells (VSMCs) in atherosclerosis plaques generate Pi and not PPi, which may exacerbate plaque calcification.


Assuntos
Aterosclerose/genética , Transdiferenciação Celular/genética , Difosfatos/metabolismo , Calcificação Vascular/genética , Trifosfato de Adenosina , Fosfatase Alcalina/genética , Animais , Aorta/citologia , Aorta/metabolismo , Ácido Ascórbico/farmacologia , Aterosclerose/metabolismo , Aterosclerose/patologia , Condrócitos/metabolismo , Condrócitos/patologia , Glicerofosfatos/genética , Glicerofosfatos/metabolismo , Humanos , Espectroscopia de Ressonância Magnética , Camundongos , Músculo Liso Vascular/metabolismo , Músculo Liso Vascular/patologia , Miócitos de Músculo Liso/metabolismo , Miócitos de Músculo Liso/patologia , Fosfatos/metabolismo , Calcificação Vascular/metabolismo , Calcificação Vascular/patologia
17.
Int J Mol Sci ; 22(5)2021 Mar 04.
Artigo em Inglês | MEDLINE | ID: mdl-33806419

RESUMO

Arterial smooth muscle exhibits rhythmic oscillatory contractions called vasomotion and believed to be a protective mechanism against tissue hypoperfusion or hypoxia. Oscillations of vascular tone depend on voltage and follow oscillations of the membrane potential. Voltage-gated sodium channels (Nav), responsible for the initiation and propagation of action potentials in excitable cells, have also been evidenced both in animal and human vascular smooth muscle cells (SMCs). For example, they contribute to arterial contraction in rats, but their physiopathological relevance has not been established in human vessels. In the present study, we investigated the functional role of Nav in the human artery. Experiments were performed on human uterine arteries obtained after hysterectomy and on SMCs dissociated from these arteries. In SMCs, we recorded a tetrodotoxin (TTX)-sensitive and fast inactivating voltage-dependent INa current. Various Nav genes, encoding α-subunit isoforms sensitive (Nav 1.2; 1.3; 1.7) and resistant (Nav 1.5) to TTX, were detected both in arterial tissue and in SMCs. Nav channels immunostaining showed uniform distribution in SMCs and endothelial cells. On arterial tissue, we recorded variations of isometric tension, ex vivo, in response to various agonists and antagonists. In arterial rings placed under hypoxic conditions, the depolarizing agent KCl and veratridine, a specific Nav channels agonist, both induced a sustained contraction overlaid with rhythmic oscillations of tension. After suppression of sympathetic control either by blocking the release of catecholamine or by antagonizing the target adrenergic response, rhythmic activity persisted while the sustained contraction was abolished. This rhythmic activity of the arteries was suppressed by TTX but, in contrast, only attenuated by antagonists of calcium channels, Na+/Ca2+ exchanger, Na+/K+-ATPase and the cardiac Nav channel. These results highlight the role of Nav as a novel key element in the vasomotion of human arteries. Hypoxia promotes activation of Nav channels involved in the initiation of rhythmic oscillatory contractile activity.


Assuntos
Artérias/metabolismo , Hipóxia/metabolismo , Contração Muscular/fisiologia , Canais de Sódio Disparados por Voltagem/metabolismo , Potenciais de Ação/efeitos dos fármacos , Potenciais de Ação/fisiologia , Adulto , Animais , Artérias/efeitos dos fármacos , Canais de Cálcio/metabolismo , Células Endoteliais/efeitos dos fármacos , Células Endoteliais/metabolismo , Feminino , Humanos , Pessoa de Meia-Idade , Contração Muscular/efeitos dos fármacos , Músculo Liso Vascular/efeitos dos fármacos , Músculo Liso Vascular/metabolismo , Miócitos de Músculo Liso/efeitos dos fármacos , Miócitos de Músculo Liso/metabolismo , Trocador de Sódio e Cálcio/metabolismo , ATPase Trocadora de Sódio-Potássio/metabolismo , Tetrodotoxina/farmacologia
18.
Mol Med Rep ; 23(5)2021 05.
Artigo em Inglês | MEDLINE | ID: mdl-33760103

RESUMO

The transformation of vascular smooth muscle cells (VSMCs) into the proliferative migratory phenotype in the plaque area contributes to stable plaque formation and facilitates the pathogenesis of atherosclerosis. Stromal interaction molecule 1 (STIM1) has been identified to promote the proliferation of VSMCs, suggesting that STIM1 may be a potent target for the prevention and treatment of atherosclerosis. Bioinformatics analysis has previously predicted STIM1 as a target of microRNA (miR)­541­3p. The present study aimed to determine the effect of the miR­541­3p/STIM1 axis on the progression of atherosclerosis in vitro. Oxidized low­density lipoprotein (ox­LDL)­treated VSMCs were used as an in vitro atherosclerosis model. Cell Counting Kit­8 and Transwell migration assays were used to analyze cell viability and migration, respectively. Reverse transcription­quantitative PCR and western blotting were applied to measure mRNA and protein expression levels, respectively. The association between miR­541­3p and STIM1 was detected using a dual luciferase gene reporter assay. The results of the present study revealed that ox­LDL treatment significantly downregulated miR­541­3p expression levels and upregulated STIM1 expression levels in VSMCs. In addition, ox­LDL stimulation enhanced cell viability and migration. The overexpression of miR­541­3p significantly reversed the ox­LDL­mediated increase in cell viability and migration, whereas the knockdown of miR­541­3p expression enhanced the ox­LDL­mediated effects. STIM1 was confirmed to be a target gene of miR­541­3p in VSMCs. The knockdown of STIM1 significantly impaired the stimulatory effects of miR­541­3p knockdown on cell viability and migration. In conclusion, the findings of the present study suggested that miR­541­3p may efficiently repress VSMC viability and migration by targeting STIM1 under the treatment of ox­LDL. These results indicated that the miR­541­3p/STIM1 axis may represent a potent target to modulate VSMC viability and migration.


Assuntos
Aterosclerose/genética , MicroRNAs/genética , Proteínas de Neoplasias/genética , Placa Aterosclerótica/genética , Molécula 1 de Interação Estromal/genética , Aterosclerose/tratamento farmacológico , Aterosclerose/patologia , Linhagem Celular , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Lipoproteínas LDL/farmacologia , Músculo Liso Vascular/efeitos dos fármacos , Músculo Liso Vascular/metabolismo , Miócitos de Músculo Liso/efeitos dos fármacos , Miócitos de Músculo Liso/metabolismo , Placa Aterosclerótica/patologia
19.
Aging (Albany NY) ; 13(5): 7538-7548, 2021 02 26.
Artigo em Inglês | MEDLINE | ID: mdl-33658391

RESUMO

Pulmonary arterial hypertension (PAH) is a fatal disease whose molecular mechanism is unknown. The trimethylation of lysine 36 on histone 3 (H3K36me3) catalyzed by SETD2 and the modification of N6-methyladenine (m6A) mRNA mediated by METTL14 play important roles in a variety of normal and pathological biological processes. However, the role of these epigenetic controls in the pathogenesis of PAH remains unclear. In this study, the expression of SETD2 and METTL14 was elevated in pulmonary artery smooth muscle cells (PASMCs) of hypoxia-induced PAH mice. We further constructed a mouse model with SETD2 specific knockout in smooth muscle cells (SETD2SM22α Cre). Our results suggest that the lack of SETD2 in SMCs protected mice from hypoxia-induced PAH and significantly reduced right ventricular systolic pressure (RVSP), right ventricular/left ventricular plus septum [RV/(LV+S)] weight ratio, and pulmonary median width. In addition, the absence of SETD2 in SMCs alleviates the level of METTL14 expression and the m6A RNA methylation level in PAH SMCs. These results obtained from mice suggest that strategies that target the inhibition of SETD2/METTL14 activity may be a viable treatment for PAH in a clinical setting.


Assuntos
Metiltransferases/metabolismo , Hipertensão Arterial Pulmonar/etiologia , Animais , Metilação de DNA , Modelos Animais de Doenças , Técnicas de Silenciamento de Genes , Histonas/metabolismo , Hipertrofia Ventricular Direita/etiologia , Hipertrofia Ventricular Direita/metabolismo , Hipóxia/complicações , Hipóxia/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Músculo Liso Vascular/metabolismo , Hipertensão Arterial Pulmonar/metabolismo
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