The essential role of transient receptor potential vanilloid 1 in simvastatin‐induced activation of endothelial nitric oxide synthase and angiogenesis

Su, Kuo‐Hui; Lin, Shing‐Jong; Wei, Jeng; Lee, K.-I.; Zhao, Jin‐Feng; Shyue, Song Kun; Lee, T.-S.

doi:10.1111/apha.12378

Cited by 58 publications

(64 citation statements)

References 40 publications

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“…TRP channels, as Ca 2+ -permeable channels, play a beneficial role in cardiovascular diseases. Moreover, the TRPV1 channel has been included in the activation of eNOS in several previous studies (40)(41)(42)(43). The present study demonstrated that TRPV1 overexpression increased the phosphorylation of eNOS in the myocardium from isoproterenol-treated mice.…”

Section: Discussionsupporting

confidence: 70%

Transgenic overexpression of transient receptor potential vanilloid subtype 1 attenuates isoproterenol-induced myocardial fibrosis in mice

Wang

Zhang

et al. 2016

International Journal of Molecular Medicine

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Abstract. Transient receptor potential vanilloid subtype 1 (TRPV1) is a non-selective cation channel with high permeability to Ca 2+. Intracellular Ca 2+ signaling is an essential regulator of endothelial nitric oxide (NO) synthase (eNOS) that plays a beneficial role in myocardial fibrosis. The aim of the present study was to determine the role of TRPV1 in isoproterenol-induced myocardial fibrosis. Transgenic mice overexpressing TRPV1 were generated on a C57BL/6J genetic background. An animal model of myocardial fibrosis was created by subcutaneously injecting the mice with isoproterenol. We found that the wild-type mice exhibited a significant increase in heart/body weight ratio, left ventricle/body weight ratio, left ventricular end-diastolic pressure (LVEDP), the cardiac fibrotic lesion area and collagen content, as well as a marked decrease in eNOS phosphorylation and NO/cyclic guanosine monophosphate (cGMP) levels at 2 weeks after the administration of isoproterenol (all p<0.01). However, these changes were significantly attenuated in the TRPV1 transgenic mice (p<0.05 or p<0.01). Moreover, the beneficial effects on myocardial fibrosis exerted by the overexpression of TRPV1 were attenuated by the administration of the eNOS inhibitor, Nω-nitro-L-arginine methyl ester (L-NAME) (all p<0.05). Similar anti-fibrotic effects were observed in in vitro experiments with primary cultured cardiac fibroblasts. The findings of our study suggest that TRPV1 overexpression attenuates isoproterenol-induced myocardial fibrosis.

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Section: Discussionsupporting

confidence: 70%

Transgenic overexpression of transient receptor potential vanilloid subtype 1 attenuates isoproterenol-induced myocardial fibrosis in mice

Wang

Zhang

et al. 2016

International Journal of Molecular Medicine

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“…Treatment with statins promotes angiogenesis in ischemic limbs of normocholesterolemic animals 3. At cellular and molecular levels, simvastatin increases endothelial nitric oxide (eNOS) activity and leads to NO production in endothelial cells (ECs) by regulating a kinase‐dependent pathway and protein‐protein interaction 6, 7. Despite many achievements of statins in treating cardiovascular complications,3, 8, 9, 10 such treatment is not always effective in improving EC function and inflammation, with unclear mechanisms under some circumstances 11, 12.…”

Section: Introductionmentioning

confidence: 99%

Asymmetric Dimethylarginine Limits the Efficacy of Simvastatin Activating Endothelial Nitric Oxide Synthase

Hsu

Zhao²,

Lin

et al. 2016

JAHA

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BackgroundAsymmetric dimethylarginine (ADMA), an endogenous inhibitor of endothelial nitric oxide synthase (eNOS), is considered a risk factor for the pathogenesis of cardiovascular diseases. Simvastatin, a lipid‐lowering drug with other pleiotropic effects, has been widely used for treatment of cardiovascular diseases. However, little is known about the effect and underlying molecular mechanisms of ADMA on the effectiveness of simvastatin in the vascular system.Methods and ResultsWe conducted a prospective cohort study to enroll 648 consecutive patients with coronary artery disease for a follow‐up period of 8 years. In patients with plasma ADMA level ≥0.49 μmol/L (a cut‐off value from receiver operating characteristic curve), statin treatment had no significant effect on cardiovascular events. We also conducted randomized, controlled studies using in vitro and in vivo models. In endothelial cells, treatment with ADMA (≥0.5 μmol/L) impaired simvastatin‐induced nitric oxide (NO) production, endothelial NO synthase (eNOS) phosphorylation, and angiogenesis. In parallel, ADMA markedly increased the activity of NADPH oxidase (NOX) and production of reactive oxygen species (ROS). The detrimental effects of ADMA on simvastatin‐induced NO production and angiogenesis were abolished by the antioxidant, N‐acetylcysteine, NOX inhibitor, or apocynin or overexpression of dimethylarginine dimethylaminohydrolase 2 (DDAH‐2). Moreover, in vivo, ADMA administration reduced Matrigel plug angiogenesis in wild‐type mice and decreased simvastatin‐induced eNOS phosphorylation in aortas of apolipoprotein E–deficient mice, but not endothelial DDAH‐2‐overexpressed aortas.ConclusionsWe conclude that ADMA may trigger NOX‐ROS signaling, which leads to restricting the simvastatin‐conferred protection of eNOS activation, NO production, and angiogenesis as well as the clinical outcome of cardiovascular events.

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“…Activation of endothelial nitric oxide synthase (eNOS) depends on the formation of calcium-calmodulin complex (Su et al, 2014). However, eNOS can also be activated by phosphorylation with PI3K, a calcium-independent mechanism (Zhang et al, 2014).…”

Section: Discussionmentioning

confidence: 99%

Evaluation of antihypertensive and vasorelaxant effects of Heimia salicifolia (family: Lythraceae)

Guzmán-Hernández¹,

Segura-Cobos²,

Amato³

et al. 2018

Afr. J. Pharm. Pharmacol.

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There are reports of the presence of vasodilatory alkaloids in Heimia salicifolia extracts. The action mechanisms of the potential antihypertensive effect of such alkaloids have not however, been elucidated. The objective of the present study was to corroborate the antihypertensive and vasorelaxant activities of the isolated alkaloids from H. salicifolia, and to characterize their vasorelaxant actions. A chloroform extract (HSCE) was obtained from H. salicifolia. The alkaloids were separated by thin layer chromatography, extracted from silica gel, and evaluated using spectroscopy. The alkaloid with the most potent vasorelaxant activity was identified as lythrine. The antihypertensive effect of the HSCE was corroborated on normotensive rats and on animals with N ω -nitro-L-arginine-methyl ester (L-NAME) induced hypertension. The action mechanisms of the HSCE and lythrine were studied on isolated and perfused rat mesenteric vascular bed (MVB) preparations. HSCE administration produced a concentration-dependent relaxation, but in preparations without vascular endothelium, the relaxant response to HSCE was significantly diminished. In MVB preparations with intact vascular endothelium, pre-contracted with phenylephrine or L-NAME, perfusion with lythrine produced concentrationdependent relaxation; a similar effect was produced by acetylcholine. Wortmannin (phosphatidylinositol 3-kinase inhibitor) and methylene blue (guanylate cyclase inhibitor) decreased the relaxant effect of lythrine. These data suggest that the vascular relaxation induced by alkaloids isolated from H. salicifolia is dependent on the activation of the nitric oxide/guanylate cyclase pathway.

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The essential role of transient receptor potential vanilloid 1 in simvastatin‐induced activation of endothelial nitric oxide synthase and angiogenesis

Cited by 58 publications

References 40 publications

Transgenic overexpression of transient receptor potential vanilloid subtype 1 attenuates isoproterenol-induced myocardial fibrosis in mice

Transgenic overexpression of transient receptor potential vanilloid subtype 1 attenuates isoproterenol-induced myocardial fibrosis in mice

Asymmetric Dimethylarginine Limits the Efficacy of Simvastatin Activating Endothelial Nitric Oxide Synthase

Evaluation of antihypertensive and vasorelaxant effects of Heimia salicifolia (family: Lythraceae)

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