Calcineurin inhibition attenuates mineralocorticoid-induced cardiac hypertrophy.
BACKGROUND
It remains unclear how mineralocorticoids induce cardiac hypertrophy and fibrosis. Recently, activation of the calcium-dependent phosphatase, calcineurin, has been shown to induce cardiac hypertrophy. In the present study, we examine the role of calcineurin in mineralocorticoid-induced cardiac hypertrophy and fibrosis.


RESULTS
Uninephrectomized Wistar-Kyoto rats were placed on a 1.0% NaCl diet and treated with aldosterone (0.75 microg x h(-1)) for 6 weeks with or without the calcineurin inhibitors, FK506 (0.5 mg x kg(-1) x d(-1)) or cyclosporine A (10 mg x kg(-1) x d(-1)). The effect of the angiotensin II type 1 receptor antagonist, losartan (10 mg x kg(-1) x d(-1))on aldosterone-induced cardiac hypertrophy was also studied. Treatment with aldosterone increased the heart weight/body weight ratio, cardiomyocyte size, and collagen amount. The expression of mRNA of both type-III collagen and atrial natriuretic peptide in the heart were increased by aldosterone administration. Both calcineurin activity and its mRNA expression were also increased in aldosterone-induced hypertrophic heart. Treatment with losartan, FK506, or cyclosporine partially prevented aldosterone-induced cardiac hypertrophy and fibrosis.


CONCLUSIONS
These results suggest that calcineurin is involved in the development of cardiac hypertrophy and fibrosis induced by mineralocorticoid excess. Inhibition of calcineurin may therefore prevent cardiac hypertrophy and fibrosis in mineralocorticoid hypertension.
Takeda
Yoshiyu
Y
Second Department of Internal Medicine, Kanazawa University, Kanazawa, Japan. takeday@im2.m.kanazawa-u.ac.jp
Yoneda
Takashi
T
Demura
Masashi
M
Usukura
Mikiya
M
Mabuchi
Hiroshi
H
D000450:Aldosterone; D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000494:pharmacology; D000959:Antihypertensive Agents / Q000494:pharmacology; D009320:Atrial Natriuretic Factor / Q000235:genetics / Q000378:metabolism; D001835:Body Weight; D019703:Calcineurin / Q000378:metabolism*; D065095:Calcineurin Inhibitors; D006332:Cardiomegaly / Q000139:chemically induced / Q000378:metabolism* / Q000473:pathology / Q000517:prevention & control*; D024061:Collagen Type III / Q000378:metabolism; D016572:Cyclosporine / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005355:Fibrosis / Q000139:chemically induced / Q000473:pathology; D006321:Heart / Q000187:drug effects; D007166:Immunosuppressive Agents / Q000494:pharmacology; D019808:Losartan / Q000494:pharmacology; D008297:Male; D008901:Mineralocorticoids; D009206:Myocardium / Q000378:metabolism / Q000473:pathology; D009392:Nephrectomy; D009929:Organ Size / Q000187:drug effects; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D011921:Rats, Inbred WKY; D017673:Sodium Chloride, Dietary; D016559:Tacrolimus / Q000494:pharmacology
D000889:Anti-Arrhythmia Agents; D000959:Antihypertensive Agents; D065095:Calcineurin Inhibitors; D024061:Collagen Type III; D004791:Enzyme Inhibitors; D007166:Immunosuppressive Agents; D008901:Mineralocorticoids; D012333:RNA, Messenger; D017673:Sodium Chloride, Dietary; D000450:Aldosterone; D016572:Cyclosporine; D009320:Atrial Natriuretic Factor; D019703:Calcineurin; D019808:Losartan; D016559:Tacrolimus