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...

Protein kinase G type I (PKGI) plays a critical role in survival signaling of pre- and postconditioning downstream of cardiac cGMP. However, it is unclear whether PKGI exerts its protective effects in the cardiomyocyte or if other cardiac cell types are involved, and whether nitric oxide (NO) metabolism can target cardiomyocyte mitochondria independently of cGMP/PKGI. We tested whether protection against reperfusion injury by ischemic postconditioning (IPost), soluble guanylyl cyclase (sGC) activation and inhibition, adenosine A(2B) receptor (A(2B)AR) agonist, phosphodiesterase type-5 (PDE-5) inhibitor, or mitochondria-targeted S-nitrosothiol (MitoSNO) was affected by a cardiomyocyte-specific ablation of the PKGI gene in the mouse (CMG-KO). In situ hearts underwent 30 min of regional ischemia followed by 2 h of reperfusion. As expected, in CMG-CTRs all interventions at early reperfusion lead to profound infarct size reduction: IPost (six cycles of 10-s reperfusion and 10-s coronary occlusion) with or without treatment with the sGC inhibitor ODQ, treatment with the specific sGC activator BAY58-2667 (BAY58), the selective A(2B)AR agonist BAY60-6583 (BAY60), PDE-5 inhibitor sildenafil, and MitoSNO. MitoSNO accumulates within mitochondria, driven by the membrane potential, where it generates NO· and S-nitrosates thiol proteins. In contrast, the hearts of CMG-KO animals were not protected by BAY58 and sildenafil, whereas the protective effects of IPost, IPost with ODQ, BAY60, and MitoSNO were unaffected by the lack of PKGI. Taken together, PKGI is important for the protection against ischemia reperfusion injury afforded by sGC activation or PDE-5 inhibition. However, the beneficial effects of IPost, activation of the A(2B)AR, as well as the direct effects via mitochondrial S-nitrosation do not depend on PKGI in cardiomyocytes.

The results suggest that cGKI and Trpc1,3,6 channels are not functionally coupled in vascular SM. Deletion of Trpc6 channels impaired endothelial cGKI signalling and vasodilator tone in the aorta.