Atorvastatin ameliorates cardiac fibrosis and improves left ventricular diastolic function in hypertensive diastolic heart failure model rats.
OBJECTIVE
Clinical studies have suggested the beneficial effects of statin therapy on diastolic heart failure. However, the mechanism of the beneficial effects of statin on diastolic heart failure remains unknown. We examined the effect of atorvastatin on the cardiac function of Dahl salt-sensitive rat, a model of hypertensive diastolic heart failure.


METHODS
Dahl salt-sensitive rats were divided into three groups: the low-salt group (given standard diet), the high-salt group (given 8% NaCl diet from 7 weeks of age), and the high-salt + atorvastatin (HS + Ato) group (given 8% NaCl diet from 7 weeks of age and atorvastatin from 17 weeks of age). We evaluated left ventricular hypertrophy (LVH), fibrosis, and function by using echocardiography and histology. We also examined the expression of molecules related to fibrosis in the hearts of Dahl salt-sensitive rats and cultured rat cardiac fibroblasts.


RESULTS
Left ventricular hypertrophy, diastolic dysfunction, and cardiac fibrosis were observed in the high-salt group. Atorvastatin ameliorated cardiac fibrosis and normalized left ventricular diastolic function without altering blood pressure. Atorvastatin also decreased the expression of heat shock protein 47 (HSP47), an essential chaperone for type 1 collagen processing, without changing in expression of transforming growth factor beta. In rat cardiac fibroblast cells, atorvastatin also reduced HSP47 level induced by transforming growth factor beta. The effect of atorvastatin was reversed by mevalonate and geranylgeranyl-pyrophosphate and mimicked by Rho kinase inhibitor.


CONCLUSIONS
Atorvastatin administration ameliorates cardiac fibrosis and improves left ventricular diastolic function in Dahl salt-sensitive rats. Lowering HSP47 by atorvastatin via inhibition of Rho-Rho kinase pathway is suggested as a mechanism.
aCardiovascular Division, Department of Internal Medicine, Hyogo College of Medicine, Nishinomiya bDepartment of Pharmacy, School of Pharmacy, Hyogo University of Health Sciences, Kobe, Japan.
Hirokuni
H
Akahori
Takeshi
T
Tsujino
Yoshiro
Y
Naito
Mika
M
Matsumoto
Naoko
N
Sasaki
Toshihiro
T
Iwasaku
Akiyo
A
Eguchi
Hisashi
H
Sawada
Shinichi
S
Hirotani
Tohru
T
Masuyama
D000818:Animals; D000069059:Atorvastatin; D002478:Cells, Cultured; D004195:Disease Models, Animal; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism; D005355:Fibrosis; D050958:HSP47 Heat-Shock Proteins / Q000378:metabolism; D054144:Heart Failure, Diastolic / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology; D006538:Heptanoic Acids / Q000494:pharmacology*; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology*; D006973:Hypertension / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology; D008297:Male; D009206:Myocardium / Q000473:pathology; D011758:Pyrroles / Q000494:pharmacology*; D051381:Rats; D020303:Rats, Inbred Dahl; D016277:Ventricular Function, Left / Q000187:drug effects; D054460:rho-Associated Kinases / Q000378:metabolism
D050958:HSP47 Heat-Shock Proteins; D006538:Heptanoic Acids; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D011758:Pyrroles; C494662:Serpinh1 protein, rat; D000069059:Atorvastatin; D054460:rho-Associated Kinases