<b>Effects of simvastatin on pulmonary fibrosis, pulmonary hypertension and exercise capacity in bleomycin‐treated rats</b>

Schroll, Stephan; Lange, Tobias; Arzt, Michael; Sebah, Daniela; Nowrotek, A.; Lehmann, H.; Wensel, Roland; Pfeifer, Michael; Blumberg, Friedrich C.

doi:10.1111/apha.12085

Cited by 20 publications

(12 citation statements)

References 68 publications

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“…Furthermore, recent studies associate statin use with the induction of pulmonary fibrosis 30 . Here we show that simvastatin can reduce the induction of pulmonary fibrosis caused by an atherogenic diet, and these effects of statin therapy on pulmonary fibrosis are supported in other models 31 – 33 . Thus, further studies aimed at understanding the mechanisms involved with simvastatin use in pulmonary fibrosis are warranted.…”

Section: Discussionsupporting

confidence: 70%

Simvastatin impairs the induction of pulmonary fibrosis caused by a western style diet: a preliminary study

Kružliak

Hare

Zvoníček

et al. 2015

J Cellular Molecular Medi

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The role of an atherogenic diet in causing pulmonary fibrosis has received little attention and simvastatin has been shown to reduce pulmonary fibrosis in animal models. To determine if an atherogenic diet can induce pulmonary fibrosis and whether simvastatin treatment is beneficial by up-regulating heat shock protein 70 and 90. New Zealand white rabbits (n = 15) were divided: Group 1 (control); Group 2 (MC) received a normal rabbit diet with 1% methionine plus 0.5% cholesterol (atherogenic diet). Group 3 received the same diet as the MC group plus 5 mg/kg/day simvastatin orally (MCS). After 4 weeks, the lungs were collected and analysed. Picrosirus red staining of lung interstitial collagen content showed that the atherogenic diet increased fibrosis 2.9-fold (P < 0.05), bronchiole adventitial collagen was increased 2.3-fold (P < 0.05) and bronchiole epithelium was increased 34-fold (P < 0.05), and simvastatin treatment severely reduced this effect (P < 0.05). Western blot analysis showed that the atherogenic diet significantly reduced lung Hsp70 protein by 22% (P < 0.05) and Hsp90 protein by 18% (P < 0.05) and simvastatin treatment did not affect this result. However, aortic hyper-responsiveness to vasoconstrictors (angiotensin II and phenylephrine) were markedly reduced by simvastatin treatment. We report that an atherogenic diet stimulates pulmonary fibrosis and reduces lung Hsp70/Hsp90 protein concentration. Simvastatin impairs this by mechanisms unrelated to Hsp70/Hsp90, but possibly a reduction in angiotensin II receptor or alpha adrenergic receptor pathways. These results could have implications in idiopathic pulmonary fibrosis.

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Section: Discussionsupporting

confidence: 70%

Simvastatin impairs the induction of pulmonary fibrosis caused by a western style diet: a preliminary study

Kružliak

Hare

Zvoníček

et al. 2015

J Cellular Molecular Medi

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“…Endothelial dysfunction is known to be a key event in the development of atherosclerosis. Statins are known to improve endothelial dysfunction by increasing eNOS activation and thus reduce cardiovascular morbidity and mortality in patients with coronary heart disease 5 6 7 8 . In this study, our findings suggest sEH phosphatase serves as a negative regulator in the simvastatin-induced eNOS activation.…”

Section: Discussionmentioning

confidence: 99%

“…Simvastatin is used to treat hyperlipidemia and related cardiovascular diseases 2 3 4 . Besides its beneficial effect on dyslipidemia, simvastatin has cholesterol-independent pleiotropic effects on the physiological function of endothelial cells (ECs) by increasing endothelial nitric oxide synthase (eNOS) activity and nitric oxide (NO) production 5 6 7 8 .…”

mentioning

confidence: 99%

Role of phosphatase activity of soluble epoxide hydrolase in regulating simvastatin-activated endothelial nitric oxide synthase

Hou

Liao

Hsiao

et al. 2015

Sci Rep

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Soluble epoxide hydrolase (sEH) has C-terminal epoxide hydrolase and N-terminal lipid phosphatase activity. Its hydrolase activity is associated with endothelial nitric oxide synthase (eNOS) dysfunction. However, little is known about the role of sEH phosphatase in regulating eNOS activity. Simvastatin, a clinical lipid-lowering drug, also has a pleiotropic effect on eNOS activation. However, whether sEH phosphatase is involved in simvastatin-activated eNOS activity remains elusive. We investigated the role of sEH phosphatase activity in simvastatin-mediated activation of eNOS in endothelial cells (ECs). Simvastain increased the phosphatase activity of sEH, which was diminished by pharmacological inhibitors of sEH phosphatase. In addition, pharmacological inhibition of sEH phosphatase or overexpressing the inactive phosphatase domain of sEH enhanced simvastatin-induced NO bioavailability, tube formation and phosphorylation of eNOS, Akt, and AMP-activated protein kinase (AMPK). In contrast, overexpressing the phosphatase domain of sEH limited the simvastatin-increased NO biosynthesis and eNOS phosphorylation at Ser1179. Simvastatin evoked epidermal growth factor receptor–c-Src–increased Tyr phosphorylation of sEH and formation of an sEH–Akt–AMPK–eNOS complex, which was abolished by the c-Src kinase inhibitor PP1 or c-Src dominant-negative mutant K298M. These findings suggest that sEH phosphatase activity negatively regulates simvastatin-activated eNOS by impeding the Akt–AMPK–eNOS signaling cascade.

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“…W. Kim, et al, 2010; Ou, et al, 2008; Schroll, et al, 2013), contrary to the findings by Xu et al (J. F. Xu, et al, 2012).…”

Section: Pulmonary Diseasementioning

confidence: 77%

Targeting the mevalonate cascade as a new therapeutic approach in heart disease, cancer and pulmonary disease

Yeganeh

Wiechec

Ande

et al. 2014

Pharmacology & Therapeutics

139

129

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The cholesterol biosynthesis pathway, also known as the mevalonate (MVA) pathway, is an essential cellular pathway that is involved in diverse cell functions. The enzyme 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase (HMGCR) is the rate-limiting step in cholesterol biosynthesis and catalyzes the conversion of HMG-CoA to MVA. Given its role in cholesterol and isoprenoid biosynthesis, the regulation of HMGCR has been intensely investigated. Because all cells require a steady supply of MVA, both the sterol (i.e. cholesterol) and non-sterol (i.e. isoprenoid) products of MVA metabolism exert coordinated feedback regulation on HMGCR through different mechanisms. The proper functioning of HMGCR as the proximal enzyme in the MVA pathway is essential under both normal physiologic conditions and in many diseases given its role in cell cycle pathways and cell proliferation, cholesterol biosynthesis and metabolism, cell cytoskeletal dynamics and stability, cell membrane structure and fluidity, mitochondrial function, proliferation, and cell fate. The blockbuster statin drugs (‘statins’) directly bind to and inhibit HMGCR, and their use for the past thirty years has revolutionized the treatment of hypercholesterolemia and cardiovascular diseases, in particular coronary heart disease. Initially thought to exert their effects through cholesterol reduction, recent evidence indicates that statins also have pleiotropic immunomodulatory properties independent of cholesterol lowering. In this review we will focus on the therapeutic applications and mechanisms involved in the MVA cascade including Rho GTPase and Rho kinase (ROCK) signaling, statin inhibition of HMGCR, geranylgeranyltransferase (GGTase) inhibition, and farnesyltransferase (FTase) inhibition in cardiovascular disease, pulmonary diseases (e.g. asthma and chronic obstructive pulmonary disease (COPD), and cancer.

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Effects of simvastatin on pulmonary fibrosis, pulmonary hypertension and exercise capacity in bleomycin‐treated rats

Cited by 20 publications

References 68 publications

Simvastatin impairs the induction of pulmonary fibrosis caused by a western style diet: a preliminary study

Simvastatin impairs the induction of pulmonary fibrosis caused by a western style diet: a preliminary study

Role of phosphatase activity of soluble epoxide hydrolase in regulating simvastatin-activated endothelial nitric oxide synthase

Targeting the mevalonate cascade as a new therapeutic approach in heart disease, cancer and pulmonary disease

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