Role of AT1 receptor in isoproterenol-induced cardiac hypertrophy and oxidative stress in mice.
Elevated activities of the sympathetic nerve and renin-angiotensin systems are common features of heart failure. This study was designed to investigate the roles of the AT1 receptor in cardiac hypertrophy and oxidative stress during excessive beta-adrenoceptor stimulation using an AT1 receptor antagonist (ARB) and AT1a receptor-deficient (AT1aR(-/-)) mice. Isoproterenol (ISO) was given to C57BL mice with or without ARB (olmesartan) treatment and to AT1aR(-/-) mice by a subcutaneously implanted osmotic mini-pump for 11 days at a rate of 15 mg/kg/day. Chronic ISO infusion to C57BL mice caused concentric cardiac hypertrophy (sham; 4.1+/-0.1, ISO; 5.2+/-0.2 mg/g heart to body weight ratio), accompanied by enhancement of cardiac collagen accumulation, lipid peroxidation, superoxide generation and NADPH oxidase activity. The AT1a and beta-1,2 receptor mRNA expressions were down-regulated in the heart of ISO-infused mice. Olmesartan markedly suppressed cardiac mass enlargement as well as increases of oxidative indicators without any effects on heart rate. Olmesartan did not affect the cardiac angiotensin and beta-adrenergic receptor mRNA expression patterns. The AT1a receptor contribution to ISO-induced cardiac hypertrophy was reproduced in AT1aR(-/-) mice. These data suggest that the AT1 receptor plays a crucial role in the development of cardiac hypertrophy and oxidative stress under excessive beta-adrenergic stimulation, and that ARB treatment is beneficial for sympatho-excitatory cardiac hypertrophy and failure in mice.
Zhang
Guo-Xing
GX
Department of Pharmacology, Kagawa University Medical School, 1750-1 Ikenobe, Miki, Kagawa 761-0793, Japan.
Ohmori
Koji
K
Nagai
Yukiko
Y
Fujisawa
Yoshihide
Y
Nishiyama
Akira
A
Abe
Youichi
Y
Kimura
Shoji
S
D000318:Adrenergic beta-Agonists / Q000494:pharmacology*; D000809:Angiotensins / Q000235:genetics / Q000378:metabolism; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D015153:Blotting, Western / Q000379:methods; D006332:Cardiomegaly / Q000139:chemically induced / Q000378:metabolism* / Q000473:pathology; D024042:Collagen Type I / Q000378:metabolism; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism; D005355:Fibrosis / Q000209:etiology / Q000378:metabolism / Q000473:pathology; D007545:Isoproterenol / Q000009:adverse effects*; D015227:Lipid Peroxidation; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009206:Myocardium / Q000378:metabolism* / Q000473:pathology; D019255:NADPH Oxidases / Q000378:metabolism; D018384:Oxidative Stress; D044140:Receptor, Angiotensin, Type 1 / Q000235:genetics / Q000502:physiology*; D011943:Receptors, Adrenergic, beta / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013481:Superoxides / Q000378:metabolism
D000318:Adrenergic beta-Agonists; D000809:Angiotensins; D000975:Antioxidants; D024042:Collagen Type I; D017362:Cyclic AMP Response Element-Binding Protein; D044140:Receptor, Angiotensin, Type 1; D011943:Receptors, Adrenergic, beta; D013481:Superoxides; D019255:NADPH Oxidases; D007545:Isoproterenol