Attenuation of ventricular hypertrophy and fibrosis in rats by pitavastatin: potential role of the RhoA-extracellular signal-regulated kinase-serum response factor signalling pathway.
1. Inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A reductase (statins) manifest pleiotropic effects that may contribute to their therapeutic efficacy. However, the mechanism of the beneficial action of statins on cardiac hypertrophy and fibrosis remains unclear. We have now investigated this action of pitavastatin in Dahl salt-sensitive (DS) rats. 2. The DS rats progressively develop marked hypertension when fed a diet containing 8% NaCl from 7 weeks of age. These animals exhibited pronounced cardiac hypertrophy and fibrosis, as well as upregulation of fetal-type cardiac gene expression at 12 weeks of age, compared with DS rats fed a diet containing 0.3% NaCl. The abundance of mRNAs for collagen types I and III, angiotensin-converting enzyme, transforming growth factor-beta1 and connective tissue growth factor was also increased in the heart of rats on the high-salt diet. 3. Treatment of rats on the high-salt diet with a non-antihypertensive dose of pitavastatin (0.3 or 1 mg/kg per day) from 7 to 12 weeks of age attenuated the development of cardiac hypertrophy and fibrosis, as well as inhibiting the upregulation of cardiac gene expression. Pitavastatin also blocked the translocation of RhoA to the membrane fraction of the left ventricle and RhoA activation, as well as the phosphorylation of the mitogen-activated protein kinases extracellular signal-regulated kinase (ERK)-1 and ERK-2 and an increase in the DNA binding activity of serum response factor (SRF) in the heart induced by the high-salt diet. 4. These findings suggest that the effects of pitavastatin on load-induced cardiac hypertrophy and fibrosis are independent of its cholesterol-lowering action and may be mediated, at least in part, through inhibition of RhoA-ERK-SRF signalling.
Saka
Masako
M
Department of Cardiovascular Genome Science, Nagoya University School of Medicine, Nagoya, Japan.
Obata
Koji
K
Ichihara
Sahoko
S
Cheng
Xian Wu
XW
Kimata
Hirotaka
H
Noda
Akiko
A
Izawa
Hideo
H
Nagata
Kohzo
K
Yokota
Mitsuhiro
M
D000375:Aging / Q000502:physiology; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D001835:Body Weight / Q000187:drug effects; D006332:Cardiomegaly / Q000188:drug therapy*; D003094:Collagen / Q000378:metabolism; D024202:Electrophoretic Mobility Shift Assay; D048049:Extracellular Signal-Regulated MAP Kinases / Q000097:blood* / Q000235:genetics; D005355:Fibrosis / Q000473:pathology; D015870:Gene Expression / Q000187:drug effects; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000627:therapeutic use*; D006973:Hypertension / Q000139:chemically induced / Q000150:complications* / Q000503:physiopathology; D017379:Hypertrophy, Left Ventricular / Q000473:pathology / Q000517:prevention & control; D015151:Immunoblotting; D008055:Lipids / Q000097:blood; D008297:Male; D009206:Myocardium / Q000473:pathology*; D011804:Quinolines / Q000627:therapeutic use*; D051381:Rats; D020303:Rats, Inbred Dahl; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D012965:Sodium Chloride; D020742:rhoA GTP-Binding Protein / Q000097:blood* / Q000235:genetics
D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D008055:Lipids; D011804:Quinolines; D012965:Sodium Chloride; D003094:Collagen; D048049:Extracellular Signal-Regulated MAP Kinases; D020742:rhoA GTP-Binding Protein; C108475:pitavastatin