Guanylyl Cyclase-A Inhibits Angiotensin II Type 1A Receptor-Mediated Cardiac Remodeling, an Endogenous Protective Mechanism in the Heart

Abstract

Background-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 1A (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 the 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 ␤ 1 and ␤ 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.

Angiotensin II type 1 receptor-independent beneficial effects of telmisartan on dietary-induced obesity, insulin resistance and fatty liver in mice

“…Male At1a-KO mice on a C57BL/6J background were generated by methods that have been described previously [6]. Animals (8 weeks of age) were divided into three groups (n=8- receiving the HFD were also administered telmisartan (3 mg/kg suspended in 5% (wt/vol.)…”

Npr1-regulated gene pathways contributing to cardiac hypertrophy and fibrosis

“…Cardiac hypertrophy and fibrosis in Npr1K/K mice have been partially ascribed to activation of the angiotensin 1 receptor (AT1R; Li et al 2002Li et al , 2004. The calcineurin-nuclear factor of activated T cells (NFAT) pathway mediates AT1R signalling and has also been implicated since blockade of calcineurin activation significantly ameliorated the cardiac hypertrophy and the activation of cardiac gene expression in Npr1 knockout mice (Tokudome et al 2005).…”

Effects of Continuous Infusion of Low-dose Human Atrial Natriuretic Peptide (hANP) on the Lungs during Cardiac Surgery

“…2,[5][6][7][8][9][10][11][12] It is also used as a drug for acute heart failure, as it has an effect to improve acute-phase hemodynamics. Furthermore, based on clinical findings suggesting that the agent might have a cardioprotective effect in patients with acute myocardial infarction, a cardioprotective action that goes beyond hemodynamic improvement in the acute phase is also expected.…”

“…[2][3][4][5][6][7] ANP has been demonstrated to exert various effects, including inhibition of the renin-angiotensin-aldosterone system, reduced myocardial hypertrophy, improved cardiac function, and less remodeling, and fibrosis. [8][9][10][11][12] During cardiac operations performed in our department, we have administered an intravenous infusion of lowdose ANP at the onset of cardiopulmonary bypass (CPB)…”