Cardiac hypertrophy is not amplified by deletion of cGMP-dependent protein kinase I in cardiomyocytes

Abstract

It has been suggested that cGMP kinase I (cGKI) dampens cardiac hypertrophy. We have compared the effect of isoproterenol (ISO) and transverse aortic constriction (TAC) on hypertrophy in WT [control (CTR)] mice, total cGKI-KO mice, and cGKIβ rescue mice (βRM) lacking cGKI specifically in cardiomyocytes (CMs). Infusion of ISO did not change the expression of cGKI in the hearts of CTR mice or βRM but raised the heart weight by ∼20% in both. An identical hypertrophic growth response was measured in CMs from CTR mice and βRM and in isolated adult CMs cultured with or without 1 μM ISO. In both genotypes, ISO infusion induced similar changes in the expression of hypertrophy-associated cardiac genes and significant elevation of serum atrial natriuretic peptide and total cardiac cGMP. No differences in cardiac hypertrophy were obtained by 7-day ISO infusion in 4-to 6-week-old conventional cGKI-KO and CTR mice. Furthermore, TAC-induced hypertrophy of CTR mice and βRM was not different and did not result in changes of the cGMP-hydrolyzing phosphodiesterase activities in hypertropic hearts or CMs. These results strongly suggest that cardiac myocyte cGKI does not affect the development of heart hypertrophy induced by pressure overload or chronic ISO infusion.cyclic nucleotides | phosphodiesterase | phosphorylation | transverse aortic constriction | sildenafil C linical studies and genetically modified mice have supported the notion that natriuretic peptides (NPs), the particulate guanylyl cyclase (GC)-A, and the second messenger cGMP can attenuate the development of pressure-or volume-induced cardiac hypertrophy and fibrosis (1). Disruption of the murine GC-A gene, the receptor for the cardiac "hormones" atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP), results in salt-resistant elevation of blood pressure, cardiac fibrosis, and hypertrophy (2, 3). To a great extent, hypertrophy is independent of blood pressure elevation (4, 5) but is enhanced transverse aortic constriction (TAC) in the absence of GC-A (4). Further studies using cardiac muscle-specific deletion of GC-A confirmed that cardiac muscle hypertrophy is independent of changes in blood pressure (6). ANP, nitric oxide (NO) donors, and 8-Br-cGMP inhibited norepinephrine-induced hypertrophy of cardiac cells and fibroblasts (7,8).Although it is recognized that GC-A-deficient hearts exhibit marked hypertrophy with interstitial fibrosis (2, 9), deletion of ANP did not result in obvious hypertrophy and fibrosis (10). Other reports have indicated that ANP ablation in mice causes an accelerated susceptibility to hypertrophy induced by different stress stimuli (11,12). Obviously, ANP and BNP secreted by the cardiomyocytes (CMs) act as paracrine factors that exert antifibrotic effects in vivo and play a role as local regulators of ventricular remodeling. Furthermore, it has been shown that rats expressing a dominant-negative mutant of GC-B and having an attenuated cGMP response to C-natriuretic peptide and a normal response to ANP showed marked cardiac hyp...

Roles of cGMP-dependent protein kinase I (cGKI) and PDE5 in the regulation of Ang II-induced cardiac hypertrophy and fibrosis

“…1D). This result suggests, in agreement with our previous findings (22), that the absence of cGKI in the CMs and ECs of the heart does not increase the extent of cardiac hypertrophy, at least under normal physiological conditions.…”

“…This result strongly suggests the major effects of sildenafil on these parameters are due to effects outside of the SMCs and CMFs. (iv) Similarly to what has been observed with isoproterenol infusion and aortic constriction (22), AII-induced hypertrophy was not augmented and, if anything, slightly reduced in βRM compared with WT mice despite an increase in fibrosis (Fig. 4).…”

“…(24). Chronic infusion of isoproterenol or TAC induced in βRM mice a cardiac hypertrophy that was identical to that of WT littermate controls (22), a result that argues against the hypothesis that CM, EC, or CF cGKI is responsible for the antihypertrophic effects of cGMP in the heart. To examine the role(s) of sildenafil to inhibit cardiac hypertrophy and fibrosis, we now extend these experiments using AII-induced hypertrophy and high concentrations of sildenafil (0.6 mM) in the drinking water.…”

“…We (22) and others (23) have tested the hypothesis that CMcGKI attenuates cardiac hypertrophy by using the cGKIβ rescue mouse line (βRM). These animals express the cGKIβ isozyme under the SM22α promoter, which is active principally in SMCs and activated CMFs, but do not express cGKIβ in other cell types…”

Newly Identified NO‐Sensor Guanylyl Cyclase/Connexin 43 Association Is Involved in Cardiac Electrical Function

“…Binding of NO to the heme of GC1 increases the catalytic activity >50‐fold. The NO‐GC1‐cGMP pathway regulates numerous cardiovascular functions, including vascular tone and cardiac homeostasis, mostly through activation of protein kinase G. Specifically in the heart, the NO‐cGMP signaling has a well‐established cardioprotective effect against hypertrophy, acute ischemia/reperfusion injury, and heart failure 1. In isolated cardiomyocytes from systemic GCα1 knockout (GCα1‐KO) mice, a model used herein, it was shown that GC1 modulates cardiac contractility by mediating both negative and positive ionotropic effects, under β3 adrenergic stimulation and basal condition, respectively 2.…”