title: Fluvastatin decreases cardiac fibrosis possibly through regulation of TGF-beta(1)/Smad 7 expression in the spontaneously hypertensive rats.
abstract: Statins ameliorate myocardial fibrosis after myocardial infarction. We designed this study to determine whether fluvastatin reduced hypertension-induced myocardial hypertrophy and fibrosis and whether these fluvastatin effects involved transforming growth factor beta1 (TGF-beta1) and Smad 7, factors known to play a role in the myocardial hypertrophy and fibrosis. We randomized 14 week old spontaneously hypertensive rats (SHRs) to receiving vehicle or 5-20 mg/kg/day fluvastatin for 8 weeks. Wistar Kyoto (WKY) rats receiving vehicle or 10 mg/kg/day fluvastatin were also studied. SHRs had an increased blood pressure, left ventricular hypertrophy and fibrosis compared with WKY rats. SHRs also had an elevated TGF-beta1 expression and a decreased Smad 7 expression. These changes in SHRs were dose-dependently attenuated by fluvastatin. For example, the hydroxyproline content was 3.2+/-0.1, 4.0+/-0.1 and 3.5+/-0.1 microg/mg heart and the Smad 7 protein expression was 5.1+/-0.6, 1.0+/-0.1 and 4.1+/-0.7 arbitrary units for WKY rats, SHRs and SHRs receiving 20 mg/kg/day fluvastatin, respectively. The hydroxyproline content in the SHRs treated with or without fluvastatin was positively correlated with the left ventricular mass index, systolic blood pressure and the amount of TGF-beta1 proteins and negatively correlated with the Smad 7 expression level. The left ventricular mass index was positively correlated with the systolic blood pressure. Fluvastatin did not alter the blood pressure, left ventricular mass index and collagen content of WKY rats. These results suggest that fluvastatin reduces hypertension-induced myocardial hypertrophy and fibrosis. These effects may involve an increased expression of Smad 7 and a decreased expression of TFG-beta1. Our results call for clinical studies to evaluate these fluvastatin effects in hypertensive patients.
authors.affiliation: Department of Cardiology, First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, China.
authors.forename: Yuansheng
authors.initials: Y
authors.lastname: Zhai
authors.forename: Xiuren
authors.initials: X
authors.lastname: Gao
authors.forename: Qiaomei
authors.initials: Q
authors.lastname: Wu
authors.forename: Longyun
authors.initials: L
authors.lastname: Peng
authors.forename: Jun
authors.initials: J
authors.lastname: Lin
authors.forename: Zhiyi
authors.initials: Z
authors.lastname: Zuo
mesh_terms: D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D015153:Blotting, Western; D006332:Cardiomegaly / Q000473:pathology / Q000517:prevention & control; D002784:Cholesterol / Q000097:blood; D003094:Collagen / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D005229:Fatty Acids, Monounsaturated / Q000494:pharmacology*; D005355:Fibrosis; D000077340:Fluvastatin; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology*; D006909:Hydroxyproline / Q000378:metabolism; D007150:Immunohistochemistry; D007211:Indoles / Q000494:pharmacology*; D008055:Lipids / Q000097:blood; D008297:Male; D009206:Myocardium / Q000473:pathology*; D051381:Rats; D011918:Rats, Inbred SHR; D011921:Rats, Inbred WKY; D020133:Reverse Transcriptase Polymerase Chain Reaction; D051906:Smad7 Protein / Q000096:biosynthesis* / Q000235:genetics; D053773:Transforming Growth Factor beta1 / Q000096:biosynthesis* / Q000235:genetics
chemical_list: D005229:Fatty Acids, Monounsaturated; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D007211:Indoles; D008055:Lipids; D051906:Smad7 Protein; C497808:Smad7 protein, rat; D053773:Transforming Growth Factor beta1; D000077340:Fluvastatin; D003094:Collagen; D002784:Cholesterol; D006909:Hydroxyproline