Guanylyl cyclase-A inhibits angiotensin II type 1A receptor-mediated cardiac remodeling, an endogenous protective mechanism in the heart

Article

关键词: ATRIAL-NATRIURETIC-PEPTIDE;    CONVERTING ENZYME-INHIBITION;    LEFT-VENTRICULAR HYPERTROPHY;    ACTIVATED PROTEIN-KINASE;    ALDOSTERONE SYSTEM;    DEFICIENT MICE;    NITRIC-OXIDE;    FIBROBLASTS;    MYOCYTES;    RAT;   

DOI  :  10.1161/01.CIR.0000029923.57048.61

来源: SCIE

【 摘 要 】

Back-ground-Guanylyl cyclase (GC)-A, a natriuretic peptide receptor, lowers blood pressure and inhibits the growth of cardiac myocytes and fibroblasts. Angiotensin II (Ang II) type I A (AT(1A)), an Ang II receptor, regulates cardiovascular homeostasis oppositely. Disruption of GC-A induces cardiac hypertrophy and fibrosis, suggesting that GC-A protects the heart from abnormal remodeling. We investigated whether GC-A interacts with AT(1A) signaling in die heart by target deletion and pharmacological blockade or stimulation of AT(1A) in mice. Methods and Results-We generated double-knockout (KO) mice for GC-A and AT(1A) by crossing GC-A-KO mice and AT(1A)-KO mice and blocked AT(1) with a selective antagonist, CS-866. The cardiac hypertrophy and fibrosis of GC-A-KO mice were greatly improved by deletion or pharmacological blockade of AT(1A). Overexpression of mRNAs encoding atrial natriuretic peptide, brain natriuretic peptide, collagens I and III, transforming growth factors beta(1) and beta(3), were also strongly inhibited. Furthermore, stimulation of AT(1A) by exogenous Ang II at a subpressor dose significantly exacerbated cardiac hypertrophy and dramatically augmented interstitial fibrosis in GC-A-KO mice but not in wild-type animals. Conclusions-These results suggest that cardiac hypertrophy and fibrosis of GC-A-deficient mice are partially ascribed to an augmented cardiac AT(1A) signaling and that GC-A inhibits AT(1A) signaling-mediated excessive remodeling.

【 授权许可】

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