Dysfunction of Vascular Smooth Muscle and Vascular Remodeling by Simvastatin
| Autor: | Ok-Nam Bae, Keunyoung Kim, Jin Ho Chung, Moo-Yeol Lee, Young Min Bae, Seojin Kang, Kyung Min Lim, Ji-Yoon Noh, Hyang-Hwa Woo |
|---|---|
| Rok vydání: | 2014 |
| Předmět: |
Male
Simvastatin medicine.medical_specialty Time Factors Contraction (grammar) RHOA Vascular smooth muscle Endothelium Myocytes Smooth Muscle Primary Cell Culture Aorta Thoracic Toxicology Muscle Smooth Vascular Rats Sprague-Dawley medicine.artery Internal medicine medicine Animals cardiovascular diseases Cells Cultured Aorta Dose-Response Relationship Drug biology nutritional and metabolic diseases Rats Endocrinology medicine.anatomical_structure Vasoconstriction biology.protein Calcium lipids (amino acids peptides and proteins) Hydroxymethylglutaryl-CoA Reductase Inhibitors medicine.symptom Muscle Contraction Muscle contraction medicine.drug |
| Zdroj: | Toxicological Sciences. 138:446-556 |
| ISSN: | 1096-0929 1096-6080 |
| DOI: | 10.1093/toxsci/kfu011 |
| Popis: | Statins, inhibitors of 3-hydroxy-3-methylglutaryl-coenzyme A reductase, are widely prescribed for hypercholesterolemia. With the increasing use of statins, numerous reports demonstrated that statins can cause damage to skeletal muscles. However, the toxicities of statins on vascular smooth muscle, which are essential to cardiovascular homeostasis, have not been previously described. Here, we examined the effects of simvastatin on the contractile function and the integrity of vascular smooth muscle in isolated rat thoracic aortic rings, primary cultured vascular smooth muscle cells (VSMCs) in vitro and rats in vivo. In aortic rings, simvastatin suppressed the normal agonist-induced contractile responses in time- and concentration-dependent manners (0.86 g ± 0.11 at 10 μM simvastatin for 24 h compared with 1.89 g ± 0.11 at control). The suppression persisted in the endothelium-denuded aortic rings and was irreversible even after wash-out of simvastatin. Simvastatin suppressed the contraction induced by Bay K8644, an activator of voltage-operated Ca²⁺ channel (VOCC) in rat aortic rings and abolished agonist-induced intracellular Ca²⁺ increase in VSMCs. The simvastatin-induced contractile dysfunction was reversed by the supplementation of mevalonate and geranylgeranylpyrophosphate, precursors for protein isoprenylation. Consistently, activation of RhoA, a representative isoprenylated protein, was disrupted by simvastatin in VSMCs and RhoA-mediated phosphorylation of MYPT1 and CPI-17, and tonic tension were also suppressed. Notably, prolonged treatment of simvastatin up to 48 h induced apoptosis of vascular smooth muscle in aortic rings. Most importantly, simvastatin treatment in vivo significantly attenuated the agonist-induced vasoconstriction in rats ex vivo and induced a decrease in luminal area of the vascular wall. Collectively, these results demonstrate that simvastatin can impair the normal vascular contractility by disturbing Ca²⁺ influx and RhoA activity, ultimately leading to apoptosis and structural remodeling. |
| Databáze: | OpenAIRE |
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