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1.
Molecules ; 26(14)2021 Jul 11.
Artigo em Inglês | MEDLINE | ID: mdl-34299486

RESUMO

Coptisine is the major bioactive protoberberine alkaloid found in Rhizoma Coptidis. Coptisine reduces inflammatory responses and improves glucose tolerance; nevertheless, whether coptisine has vasoprotective effect in diabetes is not fully characterized. Conduit arteries including aortas and carotid arteries were obtained from male C57BL/6J mice for ex vivo treatment with risk factors (high glucose or tunicamycin) and coptisine. Some arterial rings were obtained from diabetic mice, which were induced by high-fat diet (45% kcal% fat) feeding for 6 weeks combined with a low-dose intraperitoneal injection of streptozotocin (120 mg/kg). Functional studies showed that coptisine protected endothelium-dependent relaxation in aortas against risk factors and from diabetic mice. Coptisine increased phosphorylations of AMPK and eNOS and downregulated the endoplasmic reticulum (ER) stress markers as determined by Western blotting. Coptisine elevates NO bioavailability and decreases reactive oxygen species level. The results indicate that coptisine improves vascular function in diabetes through suppression of ER stress and oxidative stress, implying the therapeutic potential of coptisine to treat diabetic vasculopathy.


Assuntos
Berberina/análogos & derivados , Diabetes Mellitus Experimental/complicações , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Endotélio Vascular/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Doenças Vasculares/tratamento farmacológico , Doenças Vasculares/etiologia , Proteínas Quinases Ativadas por AMP/metabolismo , Animais , Aorta/efeitos dos fármacos , Aorta/metabolismo , Berberina/farmacologia , Diabetes Mellitus Experimental/metabolismo , Dieta Hiperlipídica/efeitos adversos , Endotélio Vascular/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Óxido Nítrico/metabolismo , Óxido Nítrico Sintase Tipo III/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Doenças Vasculares/metabolismo
2.
Fitoterapia ; 153: 104985, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34237389

RESUMO

Affinin is mainly recognized by its antinociceptive effect. Recently, our research group demonstrated that this compound produces vasodilation via activation of the gasotransmitters signaling pathways. However, the molecular targets of affinin were not identified. Considering the structural similarity of this alkamide with anandamide, we hypothesized that affinin-induced vasodilation could involve participation of TRP channels and cannabinoid receptors. In this work, by using the isolated rat aorta assay, we assessed involvement of TRP channels, the cannabinoid system, and the HNO-CGRP-TRPA1 pathway on the mechanism of action of affinin. Additionally, we measured NO and H2S levels elicited by affinin on rat aorta homogenates and carried out computer simulations of molecular interactions between affinin and the TRPA1 and TRPV1 channels and the CB1 receptor. Our results indicated that affinin induces an increase in aortic NO and H2S levels. We found evidence that the vasodilator effect induced by affinin involves activation of TRPA1 and TRPV1 channels and the CB1 and eCB receptors. In silico analyses showed that affinin is able to bind with high affinity to these molecular targets. Moreover, we also proved that affinin-induced vasodilation is partly mediated via activation of the HNO-TRPA1-CGRP pathway. Based on these results we propose a novel mechanism of action to explain the vasodilatory effect of affinin, which could be developed as an alternative drug to treat cardiovascular diseases.


Assuntos
Alcamidas Poli-Insaturadas/farmacologia , Receptores de Canabinoides/metabolismo , Canais de Cátion TRPV/metabolismo , Vasodilatação/efeitos dos fármacos , Animais , Aorta/efeitos dos fármacos , Sulfeto de Hidrogênio , Técnicas In Vitro , Masculino , Simulação de Acoplamento Molecular , Óxido Nítrico , Ratos , Ratos Wistar
3.
Am J Physiol Heart Circ Physiol ; 321(1): H185-H196, 2021 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-34114892

RESUMO

We assessed the efficacy of oral supplementation with the flavanoid apigenin on arterial function during aging and identified critical mechanisms of action. Young (6 mo) and old (27 mo) C57BL/6N mice (model of arterial aging) consumed drinking water containing vehicle (0.2% carboxymethylcellulose; 10 young and 7 old) or apigenin (0.5 mg/mL in vehicle; 10 young and 9 old) for 6 wk. In vehicle-treated animals, isolated carotid artery endothelium-dependent dilation (EDD), bioassay of endothelial function, was impaired in old versus young (70% ± 9% vs. 92% ± 1%, P < 0.0001) due to reduced nitric oxide (NO) bioavailability. Old mice had greater arterial reactive oxygen species (ROS) production and oxidative stress (higher nitrotyrosine) associated with greater nicotinamide adenine dinucleotide phosphate oxidase (oxidant enzyme) and lower superoxide dismutase 1 and 2 (antioxidant enzymes); ex vivo administration of Tempol (antioxidant) restored EDD to young levels, indicating ROS-mediated suppression of EDD. Old animals also had greater aortic stiffness as indicated by higher aortic pulse wave velocity (PWV, 434 ± 9 vs. 346 ± 5 cm/s, P < 0.0001) due to greater intrinsic aortic wall stiffness associated with lower elastin levels and higher collagen, advanced glycation end products (AGEs), and proinflammatory cytokine abundance. In old mice, apigenin restored EDD (96% ± 2%) by increasing NO bioavailability, normalized arterial ROS, oxidative stress, and antioxidant expression, and abolished ROS inhibition of EDD. Moreover, apigenin prevented foam cell formation in vitro (initiating step in atherosclerosis) and mitigated age-associated aortic stiffening (PWV 373 ± 5 cm/s) by normalizing aortic intrinsic wall stiffness, collagen, elastin, AGEs, and inflammation. Thus, apigenin is a promising therapeutic for arterial aging.NEW & NOTEWORTHY Our study provides novel evidence that oral apigenin supplementation can reverse two clinically important indicators of arterial dysfunction with age, namely, vascular endothelial dysfunction and large elastic artery stiffening, and prevents foam cell formation in an established cell culture model of early atherosclerosis. Importantly, our results provide extensive insight into the biological mechanisms of apigenin action, including increased nitric oxide bioavailability, normalization of age-related increases in arterial ROS production and oxidative stress, reversal of age-associated aortic intrinsic mechanical wall stiffening and adverse remodeling of the extracellular matrix, and suppression of vascular inflammation. Given that apigenin is commercially available as a dietary supplement in humans, these preclinical findings provide the experimental basis for future translational studies assessing the potential of apigenin to treat arterial dysfunction and reduce cardiovascular disease risk with aging.


Assuntos
Envelhecimento/metabolismo , Endotélio Vascular/efeitos dos fármacos , Inflamação/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Espirostanos/farmacologia , Rigidez Vascular/efeitos dos fármacos , Animais , Aorta/efeitos dos fármacos , Aorta/metabolismo , Pressão Sanguínea/efeitos dos fármacos , Pressão Sanguínea/fisiologia , Artérias Carótidas/efeitos dos fármacos , Artérias Carótidas/metabolismo , Endotélio Vascular/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Espécies Reativas de Oxigênio/metabolismo
4.
Life Sci ; 280: 119731, 2021 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-34144054

RESUMO

AIMS: Canagliflozin is an antidiabetic agent which lowers blood glucose levels by inhibiting the glucose reabsorption machinery in the proximal tubules. There have not been conducted any study on its direct impact on hypercholesterolemia and associated vascular disorders independently of blood glucose lowering activity. MATERIALS AND METHODS: Rabbits were arranged in 3 groups: Group 1 (Control): regular rabbit chow; Group 2 (HCD): 1% cholesterol-enriched chow was given to rabbits for 4 weeks; Group 3 (HCD-CANA): 1% cholesterol-enriched chow was fed to rabbits concurrently with canagliflozin (10 mg/kg/day, orally) for 4 weeks. At the end of experiment, blood and tissue samples were obtained for biochemical, histological, immunohistochemical, and vascular reactivity assessment. KEY FINDINGS: When statistically compared to Control (P < 0.05), HCD showed a significant increase in the serum triglycerides, low-density lipoprotein, total cholesterol, C-reactive protein, alkaline phosphatase, alanine aminotransferase and aspartate aminotransferase. Furthermore, a significant decrease was seen in both liver and aortic levels of glutathione peroxidase and superoxide dismutase concurrently with a significant elevation in malondialdehyde levels. Aortic levels of nitrate/nitrite ratio were significantly elevated. Acetylcholine-induced relaxation was impaired as the Emax decreased significantly in aortae. Moreover, a significant increase was seen in the level of aortic intima/media ratio. Canagliflozin treatment significantly improved vascular function, lipid profile and inflammation and reduced liver injury. SIGNIFICANCE: Our data suggest that SGLT-2 inhibition via canagliflozin not only possesses an antihyperglycemic activity, but also improves hypercholesterolemia, vascular and liver function in dietary-induced hypercholesterolemia in the rabbit.


Assuntos
Aorta/efeitos dos fármacos , Canagliflozina/uso terapêutico , Hipercolesterolemia/tratamento farmacológico , Hipoglicemiantes/uso terapêutico , Fígado/efeitos dos fármacos , Inibidores do Transportador 2 de Sódio-Glicose/uso terapêutico , Animais , Aorta/fisiopatologia , Colesterol na Dieta/efeitos adversos , Hipercolesterolemia/sangue , Hipercolesterolemia/etiologia , Hipercolesterolemia/fisiopatologia , Lipídeos/sangue , Fígado/fisiopatologia , Masculino , Coelhos
5.
Molecules ; 26(10)2021 May 11.
Artigo em Inglês | MEDLINE | ID: mdl-34064778

RESUMO

Kynurenic acid (KYNA) is derived from tryptophan, formed by the kynurenic pathway. KYNA is being widely studied as a biomarker for neurological and cardiovascular diseases, as it is found in ischemic conditions as a protective agent; however, little is known about its effect after ischemia-reperfusion in the vascular system. We induced ischemia for 30 min followed by 5 min reperfusion (I/R) in the rat aorta for KYNA evaluation using functional assays combined with proteomics. KYNA recovered the exacerbated contraction induced by phenylephrine and relaxation induced by acetylcholine or sodium nitroprussiate in the I/R aorta, with vessel responses returning to values observed without I/R. The functional recovery can be related to the antioxidant activity of KYNA, which may be acting on the endothelium-injury prevention, especially during reperfusion, and to proteins that regulate neurotransmission and cell repair/growth, expressed after the KYNA treatment. These proteins interacted in a network, confirming a protein profile expression for endothelium and neuron repair after I/R. Thus, the KYNA treatment had the ability to recover the functionality of injured ischemic-reperfusion aorta, by tissue repairing and control of neurotransmitter release, which reinforces its role in the post-ischemic condition, and can be useful in the treatment of such disease.


Assuntos
Aorta/patologia , Ácido Cinurênico/uso terapêutico , Traumatismo por Reperfusão Miocárdica/tratamento farmacológico , Traumatismo por Reperfusão Miocárdica/metabolismo , Proteômica , Acetilcolina/farmacologia , Animais , Aorta/efeitos dos fármacos , Aorta/fisiopatologia , Modelos Animais de Doenças , Ácido Cinurênico/farmacologia , Contração Miocárdica/efeitos dos fármacos , Traumatismo por Reperfusão Miocárdica/fisiopatologia , Nitroprussiato/farmacologia , Fenilefrina/farmacologia , Mapas de Interação de Proteínas/efeitos dos fármacos , Ratos Sprague-Dawley , Vasodilatação/efeitos dos fármacos
6.
Nutr Metab Cardiovasc Dis ; 31(6): 1929-1938, 2021 06 07.
Artigo em Inglês | MEDLINE | ID: mdl-33992512

RESUMO

BACKGROUND AND AIMS: Atherosclerosis is characterized by lipid deposition, oxidative stress, and inflammation in the arterial intima. Ganoderma lucidum triterpenoids (GLTs) and polysaccharides (GLPs) are traditional Chinese medicines with potential cardiovascular benefits. We aimed to comprehensively evaluate the effect of GLTs and GLPs on atherosclerosis and the associated underlying mechanisms in vivo and in vitro. METHODS AND RESULTS: Japanese big-ear white rabbits were randomly divided into three groups of blank, model, and treatment, and the treatment group was fed with GLSO and GLSP (0.3 g/kg body-weight/day) for 4 months. Serum levels of triglyceride (TG), total (TC), and low density lipoprotein cholesterol (LDL-C) in GL treatment group were significantly lower than those in the model group. The area of aortic plaques was significantly reduced in the treatment group. Further, GL administration in oxidized low-density lipoprotein (ox-LDL) stimulated human umbilical vein endothelial cells (HUVECs) reduced the generation of reactive oxygen species (ROS) and malondialdehyde (MDA) by inhibiting the upregulation of the nuclear transcription factor (NF)-κB p65 and the relative receptor LOX-1. In THP-1 cells treated with phorbol myristate acetate, GL inhibited the inflammatory polarization of macrophages (as evidenced by reduced TNF-α levels) via regulation of Notch1 and DLL4 pathways. Ox-LDL-stimulated THP-1 cells treated with GL showed an increase in the apoptosis of foam cells. CONCLUSIONS: GLTs and GLPs attenuated the progression of atherosclerosis by alleviating endothelial dysfunction and inflammatory polarization of macrophages, thus promoting apoptosis of foam cells.


Assuntos
Anti-Inflamatórios/farmacologia , Antioxidantes/farmacologia , Aorta/efeitos dos fármacos , Doenças da Aorta/prevenção & controle , Aterosclerose/prevenção & controle , Células Espumosas/efeitos dos fármacos , Placa Aterosclerótica , Polissacarídeos/farmacologia , Triterpenos/farmacologia , Animais , Anti-Inflamatórios/isolamento & purificação , Antioxidantes/isolamento & purificação , Aorta/metabolismo , Aorta/patologia , Doenças da Aorta/metabolismo , Doenças da Aorta/patologia , Apoptose/efeitos dos fármacos , Aterosclerose/metabolismo , Aterosclerose/patologia , Proliferação de Células/efeitos dos fármacos , Citocinas/metabolismo , Dieta Hiperlipídica , Modelos Animais de Doenças , Feminino , Células Espumosas/metabolismo , Células Espumosas/patologia , Células Endoteliais da Veia Umbilical Humana/efeitos dos fármacos , Células Endoteliais da Veia Umbilical Humana/metabolismo , Células Endoteliais da Veia Umbilical Humana/patologia , Humanos , Mediadores da Inflamação/metabolismo , Masculino , Estresse Oxidativo/efeitos dos fármacos , Polissacarídeos/isolamento & purificação , Coelhos , Espécies Reativas de Oxigênio/metabolismo , Reishi/química , Células THP-1 , Triterpenos/isolamento & purificação
7.
Nat Commun ; 12(1): 2628, 2021 05 11.
Artigo em Inglês | MEDLINE | ID: mdl-33976159

RESUMO

Thoracic aortic aneurysm, as occurs in Marfan syndrome, is generally asymptomatic until dissection or rupture, requiring surgical intervention as the only available treatment. Here, we show that nitric oxide (NO) signaling dysregulates actin cytoskeleton dynamics in Marfan Syndrome smooth muscle cells and that NO-donors induce Marfan-like aortopathy in wild-type mice, indicating that a marked increase in NO suffices to induce aortopathy. Levels of nitrated proteins are higher in plasma from Marfan patients and mice and in aortic tissue from Marfan mice than in control samples, indicating elevated circulating and tissue NO. Soluble guanylate cyclase and cGMP-dependent protein kinase are both activated in Marfan patients and mice and in wild-type mice treated with NO-donors, as shown by increased plasma cGMP and pVASP-S239 staining in aortic tissue. Marfan aortopathy in mice is reverted by pharmacological inhibition of soluble guanylate cyclase and cGMP-dependent protein kinase and lentiviral-mediated Prkg1 silencing. These findings identify potential biomarkers for monitoring Marfan Syndrome in patients and urge evaluation of cGMP-dependent protein kinase and soluble guanylate cyclase as therapeutic targets.


Assuntos
Aneurisma da Aorta Torácica/patologia , Proteína Quinase Dependente de GMP Cíclico Tipo I/metabolismo , Síndrome de Marfan/complicações , Guanilil Ciclase Solúvel/metabolismo , Animais , Aorta/citologia , Aorta/diagnóstico por imagem , Aorta/efeitos dos fármacos , Aorta/patologia , Aneurisma da Aorta Torácica/diagnóstico , Aneurisma da Aorta Torácica/etiologia , Aneurisma da Aorta Torácica/prevenção & controle , Biomarcadores/sangue , Biomarcadores/metabolismo , Carbazóis/administração & dosagem , GMP Cíclico/sangue , GMP Cíclico/metabolismo , Modelos Animais de Doenças , Feminino , Fibrilina-1/genética , Técnicas de Silenciamento de Genes , Humanos , Masculino , Síndrome de Marfan/sangue , Síndrome de Marfan/genética , Síndrome de Marfan/patologia , Camundongos , Músculo Liso Vascular/citologia , Mutação , Miócitos de Músculo Liso , Óxido Nítrico/metabolismo , Doadores de Óxido Nítrico/administração & dosagem , Cultura Primária de Células , Guanilil Ciclase Solúvel/antagonistas & inibidores , Ultrassonografia
8.
Biomolecules ; 11(3)2021 03 11.
Artigo em Inglês | MEDLINE | ID: mdl-33799860

RESUMO

Dopamine receptors (DRs) are generally considered as mediators of vasomotor functions. However, when used in pharmacological studies, dopamine and/or DR agonists may not discriminate among different DR subtypes and may even stimulate alpha1 and beta-adrenoceptors. Here, we tested the hypothesis that D2R and/or D3R may specifically induce vasoconstriction in isolated mouse aorta. Aorta, isolated from wild-type (WT) and D3R-/- mice, was mounted in a wire myograph and challenged with cumulative concentrations of phenylephrine (PE), acetylcholine (ACh), and the D3R agonist 7-hydrxy-N,N-dipropyl-2-aminotetralin (7-OH-DPAT), with or without the D2R antagonist L741,626 and the D3R antagonist SB-277011-A. The vasoconstriction to PE and the vasodilatation to ACh were not different in WT and D3R-/-; in contrast, the contractile responses to 7-OH-DPAT were significantly weaker in D3R-/-, though not abolished. L741,626 did not change the contractile response induced by 7-OH-DPAT in WT or in D3R-/-, whereas SB-277011-A significantly reduced it in WT but did not in D3R-/-. D3R mRNA (assessed by qPCR) was about 5-fold more abundant than D2R mRNA in aorta from WT and undetectable in aorta from D3R-/-. Following transduction with lentivirus (72-h incubation) delivering synthetic microRNAs to specifically inactivate D2R (LV-miR-D2) or D3R (LV-miR-D3), the contractile response to 7-OH-DPAT was unaffected by LV-miR-D2, while it was significantly reduced by LV-miR-D3. These data indicate that, at least in mouse aorta, D3R stimulation induces vasoconstriction, while D2R stimulation does not. This is consistent with the higher expression level of D3R. The residual vasoconstriction elicited by high concentration D3R agonist in D3R-/- and/or in the presence of D3R antagonist is likely to be unrelated to DRs.


Assuntos
Aorta/fisiologia , Receptores de Dopamina D3/metabolismo , Vasoconstrição/genética , Animais , Aorta/efeitos dos fármacos , Indóis/farmacologia , Masculino , Camundongos Endogâmicos C57BL , Camundongos Knockout , Nitrilas/farmacologia , Piperidinas/farmacologia , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Receptores de Dopamina D2/genética , Receptores de Dopamina D2/metabolismo , Receptores de Dopamina D3/agonistas , Receptores de Dopamina D3/antagonistas & inibidores , Receptores de Dopamina D3/genética , Tetra-Hidroisoquinolinas/farmacologia , Tetra-Hidronaftalenos/farmacologia , Vasoconstrição/efeitos dos fármacos
9.
Biochem Biophys Res Commun ; 557: 334-341, 2021 06 11.
Artigo em Inglês | MEDLINE | ID: mdl-33915432

RESUMO

Atherosclerosis is a chronic lipid disfunction and inflammatory disease, which is characterized with enriched foam cells and necrotic core underneath the vascular endothelium. Therefore, the inhibition of foam cell formation is a critical step for atherosclerosis treatment. Metformin, a first-line treatment for Type 2 diabetes, is reported to be beneficial to cardiovascular disease. However, the mechanism underlying the antiatherogenic effect of metformin remains unclear. Macrophage autophagy is reported to be a highly anti-atherogenic process that promotes the catabolism of cytosolic lipid to maintain cellular lipid homeostasis. Notably, dysfunctional autophagy in macrophages plays a detrimental role during atherogenesis. Krueppel-like factor 2 (KLF2) is an important transcription factor that functions as a key regulator of the autophagy-lysosome pathway. While the role of KLF2 in foam cell formation during the atherogenesis remains elusive. In this study, we first investigated whether metformin could protect against atherogenesis via enhancing autophagy in high fat diet (HFD)-induced apoE-/- mice. Subsequently, we further determined the molecular mechanism that whether metformin could inhibit foam cell formation by activating KLF2-mediated autophagy. We show that metformin protected against HFD-induced atherosclerosis and enhanced plaque stability in apoE-/- mice. Metformin inhibits foam cell formation and cellular apoptosis partially through enhancing autophagy. Mechanistically, metformin promotes autophagy via modulating KLF2 expression. Taken together, our study demonstrates a novel antiatherogenic mechanism of metformin by upregulating KLF2-mediated autophagy.


Assuntos
Apolipoproteínas E/genética , Aterosclerose/tratamento farmacológico , Autofagia/efeitos dos fármacos , Células Espumosas/efeitos dos fármacos , Fatores de Transcrição Kruppel-Like/metabolismo , Metformina/farmacologia , Placa Aterosclerótica/tratamento farmacológico , Animais , Aorta/efeitos dos fármacos , Aorta/metabolismo , Aorta/patologia , Apoptose/efeitos dos fármacos , Aterosclerose/genética , Aterosclerose/metabolismo , Colesterol/metabolismo , Dieta Hiperlipídica , Células Espumosas/metabolismo , Fatores de Transcrição Kruppel-Like/genética , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Masculino , Metformina/uso terapêutico , Camundongos , Camundongos Endogâmicos C57BL , Placa Aterosclerótica/genética , Placa Aterosclerótica/metabolismo , Reação em Cadeia da Polimerase em Tempo Real
10.
Arterioscler Thromb Vasc Biol ; 41(6): e338-e353, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-33792343
11.
Genes (Basel) ; 12(3)2021 03 09.
Artigo em Inglês | MEDLINE | ID: mdl-33803192

RESUMO

Acute aortic dissection is one of the most severe vascular diseases. The molecular mechanisms of aortic expansion and dissection are unclear. Clinical studies have found that statins play a protective role in aortic dissection development and therapy; however, the mechanism of statins' effects on the aorta is unknown. The Gene Expression Omnibus (GEO) dataset GSE52093, GSE2450and GSE8686 were analyzed, and genes expressed differentially between aortic dissection samples and normal samples were determined using the Networkanalyst and iDEP tools. Weight gene correlation network analysis (WGCNA), functional annotation, pathway enrichment analysis, and the analysis of the regional variations of genomic features were then performed. We found that the minichromosome maintenance proteins (MCMs), a family of proteins targeted by statins, were upregulated in dissected aortic wall tissues and play a central role in cell-cycle and mitosis regulation in aortic dissection patients. Our results indicate a potential molecular target and mechanism for statins' effects in patients with acute type A aortic dissection.


Assuntos
Aneurisma Dissecante/tratamento farmacológico , Aorta/efeitos dos fármacos , Inibidores de Hidroximetilglutaril-CoA Redutases/farmacologia , Proteínas de Manutenção de Minicromossomo/metabolismo , Ciclo Celular/efeitos dos fármacos , Células Cultivadas , Biologia Computacional/métodos , Redes Reguladoras de Genes , Células Endoteliais da Veia Umbilical Humana , Humanos
12.
Am J Physiol Heart Circ Physiol ; 320(6): H2305-H2312, 2021 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-33861146

RESUMO

Adults with metabolic syndrome (MetS) have increased fasting arterial stiffness and altered central hemodynamics that contribute, partly, to increased cardiovascular disease (CVD) risk. Although insulin affects aortic wave reflections in healthy adults, the effects in individuals with MetS are unclear. We hypothesized that insulin stimulation would reduce measures of pressure waveforms and hemodynamics in people with MetS. Thirty-five adults with obesity (27 women; 54.2 ± 6.0 yr; 37.1 ± 4.8 kg/m2) were selected for MetS (ATP III criteria) following an overnight fast. Pulse wave analysis was assessed using applanation tonometry before and after a 2-h euglycemic-hyperinsulinemic clamp (90 mg/dL, 40 mU/m2/min). Deconvolution analysis was used to decompose the aortic waveform [augmentation index corrected to heart rate of 75 beats/min (AIx@75); augmentation pressure (AP)] into backward and forward pressure components. Aerobic fitness (V̇o2max), body composition (DXA), and blood biochemistries were also assessed. Insulin significantly reduced augmentation index (AIx@75, 28.0 ± 9.6 vs. 23.0 ± 9.9%, P < 0.01), augmentation pressure (14.8 ± 6.4 vs. 12.0 ± 5.7 mmHg, P < 0.01), pulse pressure amplification (1.26 ± 0.01 vs. 0.03 ± 0.01, P = 0.01), and inflammation [high-sensitivity C-reactive protein (hsCRP): P = 0.02; matrix metallopeptidase 7 (MMP-7): P = 0.03] compared to fasting. In subgroup analyses to understand HTN influence, there were no insulin stimulation differences on any outcome. V̇o2max, visceral fat, and blood potassium correlated with fasting AIx@75 (r = -0.39, P = 0.02; r = 0.41, P = 0.03; r = -0.53, P = 0.002). Potassium levels were also associated with insulin-mediated reductions in AP (r = 0.52, P = 0.002). Our results suggest insulin stimulation improves indices of aortic reflection in adults with MetS.NEW & NOTEWORTHY This study is one of the first to investigate the effects of insulin on central and peripheral hemodynamics in adults with metabolic syndrome. We provide evidence that insulin infusion reduces aortic wave reflection, potentially through a reduction in inflammation and/or via a potassium-mediated vascular response.


Assuntos
Aorta/efeitos dos fármacos , Pressão Sanguínea/efeitos dos fármacos , Insulina/farmacologia , Síndrome Metabólica/fisiopatologia , Análise de Onda de Pulso , Rigidez Vascular/efeitos dos fármacos , Aorta/fisiopatologia , Composição Corporal , Aptidão Cardiorrespiratória , Feminino , Técnica Clamp de Glucose , Hemodinâmica/efeitos dos fármacos , Humanos , Resistência à Insulina , Masculino , Síndrome Metabólica/metabolismo , Pessoa de Meia-Idade , Consumo de Oxigênio , Rigidez Vascular/fisiologia
13.
Aging (Albany NY) ; 13(8): 11411-11432, 2021 04 04.
Artigo em Inglês | MEDLINE | ID: mdl-33839698

RESUMO

Atherosclerosis (AS)-related diseases remain among the leading causes of death worldwide. Modified Xiaoyaosan (also called Tiaogan-Liqi prescription, TGLQ), a traditional Chinese medical formulation, has been widely applied in the treatment of AS-related diseases. The aim of this study was to investigate the underlying pharmacological mechanisms of TGLQ in acting on AS. A total of 548 chemical compounds contained in TGLQ, and 969 putative targets, were collected from the Computation Platform for Integrative Pharmacology of Traditional Chinese Medicine, while 1005 therapeutic targets for the treatment of AS were obtained from the DisGeNET, TTD and CTD databases. Moreover, the 63 key targets were screened by the intersection of the targets above, and by network topological analysis. Further functional enrichment analysis showed that the key targets were significantly associated with regulation of the immune system and inflammation, improvement of lipid and glucose metabolism, regulation of the neuroendocrine system and anti-thrombosis effect. The in vivo experiments confirmed that TGLQ could reduce plasma lipid profiles and plasma inflammatory cytokines, and also inhibit AS plaque formation, within the AS model ApoE-/- mice. The in vitro experiments validated the hypothesis that TGLQ could significantly reduce intracellular lipid accumulation, suppress the production of inflammatory cytokines of macrophages induced by oxidized-LDL, and inhibit the protein expression of heat shock protein 90 and toll-like receptor 4. This study identified a list of key targets of TGLQ in the treatment of AS by applying an integrative pharmacology approach, which was validated by in vivo and in vitro experimentation.


Assuntos
Aterosclerose/tratamento farmacológico , Medicamentos de Ervas Chinesas/farmacologia , Animais , Aorta/efeitos dos fármacos , Aorta/patologia , Aterosclerose/sangue , Aterosclerose/imunologia , Aterosclerose/patologia , Citocinas/metabolismo , Modelos Animais de Doenças , Progressão da Doença , Medicamentos de Ervas Chinesas/uso terapêutico , Humanos , Inflamação/sangue , Inflamação/tratamento farmacológico , Inflamação/imunologia , Inflamação/patologia , Metabolismo dos Lipídeos/efeitos dos fármacos , Lipídeos/sangue , Masculino , Camundongos , Camundongos Knockout para ApoE , Células RAW 264.7 , Ratos
14.
Life Sci ; 278: 119560, 2021 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-33915131

RESUMO

AIMS: The structure-vasorelaxant activity relationships (SARs) assessment in previous study has found that trans-3,4,4'-trihydroxystilbene (344OH) could potentially act as a vasorelaxing agent with demonstration of over 2-fold maximal relaxation (Rmax) compared to its analogue, resveratrol. The present study focuses on the mechanism of actions and pathways employed by 344OH and compared to its analogue to further speculate the SAR of stilbenoids towards vasorelaxation. MATERIALS AND METHODS: The 344OH employed in present study was synthesized based on the protocol in previous study. The vascular responses towards the cumulative addition of 344OH were evaluated using in vitro rat aortic rings assays. KEY FINDINGS: The pEC50 and Rmax values were found to be 4.33 ± 0.05 and 106 ± 3.99%, respectively. Results showed that the vasorelaxation of 344OH were predominated by G-protein-coupled muscarinic- (M3) and ß2-adrenergic receptors, followed by PGI2/AC/cAMP- and NO/sGC/cGMP-dependent pathways. It was also identified that 344OH employed voltage-activated- (Kv), calcium-activated- (Kca) and inwardly-rectifying (Kir) potassium channels and act as an antagonist for both VOCC and IP3R while regulating the action potential in the vasculature. SIGNIFICANCE: The different position of hydroxyl substituent located in A-ring of the stilbenoid backbone in 344OH compared to resveratrol resulted in a significant difference in mechanistic actions that lead to 344OH's fast-acting and less time-dependent vasorelaxation behaviour. This has substantially increased the potential of 344OH to be developed as an effective antihypertensive drug in future. Present findings further strengthen our inferences where the SARs study approach should be carried out as the mainstream methodology in future drug development research.


Assuntos
Anti-Hipertensivos/farmacologia , Aorta/efeitos dos fármacos , Estilbenos/farmacologia , Vasodilatadores/farmacologia , Animais , Anti-Hipertensivos/química , Aorta/fisiopatologia , Descoberta de Drogas , Hipertensão/tratamento farmacológico , Hipertensão/fisiopatologia , Masculino , Ratos Sprague-Dawley , Estilbenos/química , Vasodilatação/efeitos dos fármacos , Vasodilatadores/química
15.
Biomed Pharmacother ; 139: 111567, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-33848773

RESUMO

This study was designed to determine the effectiveness of 5-(3-Hydroxybenzylidene)-2, 4, 6(1H, 3H, 5H)-pyrimidinetrione (SR-5), 5-(4-Hydroxybenzylidene)-2, 4, 6(1H, 3H, 5H)-pyrimidinetrione (SR-8), 5-(3-Chlorobenzylidene)-2, 4, 6(1H, 3H, 5H)-pyrimidinetrione (SR-9) and 5-(4-Chlorobenzylidene)-2, 4, 6(1H, 3H, 5H)-pyrimidinetrione (SR-10) against hypertension. In deoxycorticosterone acetate-salt rats, SR-5, SR-8, SR-9, and SR-10 reduced blood pressure and normalized renal functions. In isolated rat aortic rings, SR-5, SR-8, SR-9, and SR-10 relaxed phenylephrine (PE) and K+-induced contractions. The vasodilator effect was endothelium-independent. Test compounds caused a rightward shift of Ca++ and PE concentration-response curves with a reduction of maximum response. SR-5, SR-8, SR-9, and SR-10 inhibited PE peak contractions in a Ca++ free medium. In guinea-pig atria, SR5, SR-8, SR-9, and SR-10 caused a mild-to-moderate inhibition of force and rate of contractions. In the aorta and heart tissues, the test compounds enhanced glutathione-s-transferase, reduced glutathione and catalase levels, improved cellular architecture, and decreased lipid peroxidation and expression of inflammatory markers: cyclooxygenase 2, tumor necrosis factor alpha, phosphorylated c-Jun N-terminal kinase, and phosphorylated-nuclear factor kappa B, evidenced in the immunohistochemistry, enzyme-linked immunosorbent assay, western blot molecular investigations and a decreased mRNA expression of calcium channel in RT-PCR analysis. SR-5, SR-8, SR-9, and SR-10 increased the urinary output in rats and inhibited the human platelet aggregation. This study revealed that SR-5, SR-8, SR-9, and SR-10 possess BP lowering, reno-protective, vasodilatory (mediated via Ca++ antagonist, antioxidant and anti-inflammatory pathways), partial cardio-suppressant, diuretic, and antiplatelet effects, demonstrating their therapeutic potential in hypertension management.


Assuntos
Anti-Hipertensivos/farmacologia , Hipertensão/tratamento farmacológico , Pirimidinas/farmacologia , Animais , Anti-Inflamatórios não Esteroides/farmacologia , Anti-Hipertensivos/uso terapêutico , Antioxidantes/farmacologia , Aorta/efeitos dos fármacos , Cálcio/farmacologia , Desoxicorticosterona , Feminino , Cobaias , Humanos , Hipertensão/induzido quimicamente , Testes de Função Renal , Masculino , Camundongos , Contração Muscular/efeitos dos fármacos , Músculo Liso Vascular/efeitos dos fármacos , Contração Miocárdica/efeitos dos fármacos , Fenilefrina/farmacologia , Agregação Plaquetária/efeitos dos fármacos , Pirimidinas/uso terapêutico , Ratos , Ratos Sprague-Dawley , Transdução de Sinais/efeitos dos fármacos , Vasodilatadores/farmacologia
16.
Int J Biol Macromol ; 181: 847-857, 2021 Jun 30.
Artigo em Inglês | MEDLINE | ID: mdl-33862080

RESUMO

The present study demonstrates the development of polysaccharide gelatin naturapolyceutics hydrocolloidal biomatrix with cobalt nano-additives for restructuring native tissue vasculature for tissue regenerative applications. The engineered Gelatin/Aloevera mucilage polysaccharide/nanoscaled Cobalt (GAC) hydrocolloids resulted from the intermolecular interactions between the aloevera mucilage, cobalt nano-therapeutic and gelatin. GAC hydrocolloid showed enhanced thermal stability in comparison with control Gelatin/Aloevera mucilage (GA) hydrocolloid. FTIR analysis validated that the reinforcement of aloevera mucilage and cobalt nano-therapeutic did not affect the structural integrity of the gelatin molecule. 3-Dimensional sponge-like orientation of GAC hydrocolloid facilitates perfusable biomatrix for access to nutrients and gaseous exchange for high cell adhesion and proliferation. The combined therapeutic efficacy of mucilage polysaccharides, biodegradable nanoscaled cobalt and bio-polymer enhanced the pro-angiogenic capability of the hydrocolloids by stimulating Vascular Endothelial Growth Factor (VEGF) response at wounded tissue for faster healing. The experimental outcomes on in vivo angiogenesis profiling further confirmed the development of micro vessel in chick embryonic model and regeneration of blood vessels in zebra fish model. This study opens up the potential of mucilage polysaccharides in stimulating high density angiogenesis and conveys the progress of a biocompatible, biodegradable mucilaginous hydrocolloid as an effective bio-adhesive for vascular development in soft tissue regeneration.


Assuntos
Cobalto/química , Coloides/química , Gelatina/química , Glicosaminoglicanos/farmacologia , Nanopartículas/química , Neovascularização Fisiológica , Adulto , Animais , Aorta/efeitos dos fármacos , Aorta/fisiologia , Varredura Diferencial de Calorimetria , Movimento Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Galinhas , Membrana Corioalantoide/efeitos dos fármacos , Glicosaminoglicanos/química , Humanos , Neovascularização Fisiológica/efeitos dos fármacos , Ratos , Espectroscopia de Infravermelho com Transformada de Fourier , Fator A de Crescimento do Endotélio Vascular/metabolismo , Cicatrização/efeitos dos fármacos , Peixe-Zebra
17.
Int J Mol Sci ; 22(8)2021 Apr 17.
Artigo em Inglês | MEDLINE | ID: mdl-33920718

RESUMO

The opioid system is well-known for its role in modulating nociception and addiction development. However, there are premises that the endogenous opioid system may also affect blood pressure. The main goal of the present study was to determine the impact of different endogenous opioid system activity and its pharmacological blockade on blood pressure. Moreover, we examined the vascular function in hyper- and hypoactive states of the opioid system and its pharmacological modification. In our study, we used two mouse lines which are divergently bred for high (HA) and low (LA) swim stress-induced analgesia. The obtained results indicated that individuals with low endogenous opioid system activity have higher basal blood pressure compared to those with a hyperactive opioid system. Additionally, naloxone administration only resulted in the elevation of blood pressure in HA mice. We also showed that the hypoactive opioid system contributes to impaired vascular relaxation independent of endothelium, which corresponded with decreased guanylyl cyclase levels in the aorta. Together, these data suggest that higher basal blood pressure in LA mice is a result of disturbed mechanisms in vascular relaxation in smooth muscle cells. We believe that a novel mechanism which involves endogenous opioid system activity in the regulation of blood pressure will be a promising target for further studies in hypertension development.


Assuntos
Aorta/efeitos dos fármacos , Pressão Sanguínea , Naloxona/farmacologia , Antagonistas de Entorpecentes/farmacologia , Nociceptividade , Animais , Aorta/citologia , Aorta/metabolismo , Endotélio Vascular/efeitos dos fármacos , Feminino , Guanilato Ciclase/metabolismo , Masculino , Camundongos , Miócitos de Músculo Liso/efeitos dos fármacos , Vasodilatação
18.
Int J Mol Sci ; 22(7)2021 Mar 24.
Artigo em Inglês | MEDLINE | ID: mdl-33804982

RESUMO

This study aimed to examine the effect of lipid emulsion (LE) on the vasoconstriction induced by dexmedetomidine (DMT) in the isolated rat aorta and elucidate the associated cellular mechanism. The effect of LE, NW-nitro-L-arginine methyl ester (L-NAME), and methyl-ß-cyclodextrin (MßCD) on the DMT-induced contraction was examined. We investigated the effect of LE on the DMT-induced cyclic guanosine monophosphate (cGMP) formation and DMT concentration. The effect of DMT, LE, 4-Amino-3-(4-chlorophenyl)-1-(t-butyl)-1H-pyrazolo[3,4-d]pyrimidine,4-Amino-5-(4-chlorophenyl)-7-(t-butyl)pyrazolo[3,4-d]pyrimidine (PP2), and rauwolscine on the phosphorylation of endothelial nitric oxide synthase (eNOS), caveolin-1, and Src kinase was examined in the human umbilical vein endothelial cells. L-NAME, MßCD, and LE (1%, standardized mean difference (SMD): 2.517) increased the DMT-induced contraction in the endothelium-intact rat aorta. LE (1%) decreased the DMT (10-6 M) concentration (SMD: -6.795) and DMT-induced cGMP formation (SMD: -2.132). LE (1%) reversed the DMT-induced eNOS (Ser1177 and Thr496) phosphorylation. PP2 inhibited caveolin-1 and eNOS phosphorylation induced by DMT. DMT increased the Src kinase phosphorylation. Thus, LE (1%) enhanced the DMT-induced contraction by inhibition of NO synthesis, which may be caused by the decreased DMT concentration. DMT-induced NO synthesis may be caused by the increased eNOS (Ser1177) phosphorylation and decreased eNOS (Thr495) phosphorylation potentially mediated by Src kinase-induced caveolin-1 phosphorylation.


Assuntos
Aorta/efeitos dos fármacos , Dexmedetomidina/farmacologia , Emulsões , Endotélio/efeitos dos fármacos , Lipídeos/química , Vasoconstrição/efeitos dos fármacos , Animais , GMP Cíclico/metabolismo , Endotélio Vascular/metabolismo , Células Endoteliais da Veia Umbilical Humana/efeitos dos fármacos , Humanos , Masculino , NG-Nitroarginina Metil Éster/farmacologia , Óxido Nítrico Sintase Tipo III/metabolismo , Fosforilação/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley , Ioimbina/farmacologia , beta-Ciclodextrinas/química
19.
Oxid Med Cell Longev ; 2021: 8865979, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33791074

RESUMO

Polycystic ovary syndrome (PCOS) is associated with elevated cardiovascular risk. Early vascular dysfunction may lead to the development of cardiovascular disease in PCOS. Vitamin D deficiency (VDD) is a common comorbidity of PCOS that contributes to the pathogenesis of the disease and its complications. Both PCOS and VDD are accompanied by increased oxidative stress that may be involved in the arising vascular dysfunction. We aimed to investigate the role of vitamin D status on aortic function. PCOS was induced by an 8-week-long transdermal testosterone treatment of female rats, and low and adequate vitamin D status was achieved by dietary means. Contraction and relaxation abilities of isolated aortic segments were measured by myograph. Resorcin-fuchsin staining and immunohistochemical labeling of 3-nitrotyrosine were performed. No difference was shown in the norepinephrine-induced contraction of the aortas of different groups, whereas we detected reduced acetylcholine- and insulin-evoked relaxation in VDD groups. A lower level of resorcin-fuchsin staining and elevated 3-nitrotyrosine immunostaining was observed in VDD. In our study, we demonstrated early endothelial dysfunction in VDD PCOS rat model. Vitamin D supplementation could prevent vascular disturbances, while VDD itself damaged endothelium-dependent vasorelaxation and induced nitrative stress.


Assuntos
Aorta/fisiopatologia , Síndrome do Ovário Policístico/fisiopatologia , Vitamina D/farmacologia , Animais , Aorta/efeitos dos fármacos , Modelos Animais de Doenças , Feminino , Contração Muscular/efeitos dos fármacos , Ratos Wistar , Coloração e Rotulagem
20.
Nutrients ; 13(4)2021 Apr 20.
Artigo em Inglês | MEDLINE | ID: mdl-33924014

RESUMO

Evidence from animal models indicates that maternal diet during pregnancy affects offspring cardiometabolic health. Improving carbohydrate quality during high-risk pregnancies reduces aortic intima-medial thickness; a marker for early atherosclerosis; in the infant offspring. We sought to determine whether maternal carbohydrate quantity and quality are associated with newborn aortic intima-medial thickness in healthy pregnancies. Maternal diet throughout pregnancy was evaluated in 139 mother-child dyads using a validated food frequency questionnaire. Carbohydrate intake was expressed as quantity (% total energy), quality (fibre, glycaemic index), and glycaemic burden (glycaemic load). Aortic intima-medial thickness was measured by high-frequency ultrasound of the neonatal abdominal aorta. Neither quantity nor quality of maternal carbohydrate intake during pregnancy was associated with meaningful differences in offspring maximum aortic intima-medial thickness with the exception of fibre intake in women with overweight or obesity which was inversely associated (-8 µm [95% CI -14, -1] per g fibre, p = 0.04). In healthy pregnancy, the quantity and quality of maternal carbohydrate intake is likely not a meaningful modifiable lifestyle factor for influencing offspring vascular health. The effect of carbohydrate quality may only be evident in high-risk pregnancies, consistent with previous findings. These findings may be confirmed in prospective dietary trials in pregnancy.


Assuntos
Aorta/anatomia & histologia , Carboidratos da Dieta/farmacologia , Ingestão de Alimentos , Fenômenos Fisiológicos da Nutrição Materna , Adulto , Aorta/efeitos dos fármacos , Espessura Intima-Media Carotídea , Feminino , Humanos , Recém-Nascido , Análise Multivariada , Análise de Regressão
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