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

Abstract

Conflicting results have been reported for the roles of cGMP and cGMP-dependent protein kinase I (cGKI) in various pathological conditions leading to cardiac hypertrophy and fibrosis. A cardioprotective effect of cGMP/cGKI has been reported in whole animals and isolated cardiomyocytes, but recent evidence from a mouse model expressing cGKIβ only in smooth muscle (βRM) but not in cardiomyocytes, endothelial cells, or fibroblasts has forced a reevaluation of the requirement for cGKI activity in the cardiomyocyte antihypertrophic effects of cGMP. In particular, βRM mice developed the same hypertrophy as WT controls when subjected to thoracic aortic constriction or isoproterenol infusion. Here, we challenged βRM and WT (Ctr) littermate control mice with angiotensin II (AII) infusion (7 d; 2 mg·kg −1 ·d −1 ) to induce hypertrophy. Both genotypes developed cardiac hypertrophy, which was more pronounced in Ctr animals. Cardiomyocyte size and interstitial fibrosis were increased equally in both genotypes. Addition of sildenafil, a phosphodiesterase 5 (PDE5) inhibitor, in the drinking water had a small effect in reducing myocyte hypertrophy in WT mice and no effect in βRM mice. However, sildenafil substantially blocked the increase in collagen I, fibronectin 1, TGFβ, and CTGF mRNA in Ctr but not in βRM hearts. These data indicate that, for the initial phase of AII-induced cardiac hypertrophy, lack of cardiomyocyte cGKI activity does not worsen hypertrophic growth. However, expression of cGKI in one or more cell types other than smooth muscle is necessary to allow the antifibrotic effect of sildenafil.PKGI | PDE | cardiac failure | hypertension | NO/cyclic GMP system

PDE1C deficiency antagonizes pathological cardiac remodeling and dysfunction

“…To confirm this possibility, further studies using acute PDE1C depletion/inhibition and more specific PKG blockade will be required. Many studies have reported that PKG signaling has antihypertrophic functions in cardiac myocytes (39)(40)(41); however, because of the lack of effects of cardiomyocyte PKG depletion on cardiac myocyte hypertrophy and cardiac remodeling in certain models of cardiac hypertrophy and dysfunction, this notion remains somewhat controversial (42,43). The precise mechanism by which PDE1C regulates cardiac fibrosis is not clear.…”

Sildenafil Does Not Prevent Heart Hypertrophy and Fibrosis Induced by Cardiomyocyte Angiotensin II Type 1 Receptor Signaling

“…Cardiac growth responses to TAC or isoproterenol in cGKIb rescue mice were normal, suggesting either that non-SMC cGKI is not required to inhibit pressure overload-and b-adrenergic receptor-triggered remodeling or cGMP/cGKI are not appropriately activated under these experimental conditions. Therefore, we previously applied a hypertensive dose of Ang II and confirmed that antifibrotic effects of SIL (Westermann et al, 2012) were indeed related to non-SMC cGKI (Patrucco et al, 2014). The following points regarding the cellular targets of SIL/cGMP/cGKI and Ang II are still open : 1) The vasoactive neurohormone Ang II may provoke cardiac stress by changes in hemodynamics, i.e., an increase in afterload resulting from high blood pressure, and from direct effects on non-CM cells.…”

“…We examined the potentially antihypertrophic and antifibrotic roles of cGMP signaling for the (Ang II)/AT 1 R-provoked defects in the CM (Booz, 2005), as intensive cross-talk between these pathways in different settings of cardiac stresses has been reported (Li et al, 2002;Masuyama et al, 2006;Tokudome et al, 2008;Klaiber et al, 2010;Mokni et al, 2010;Frantz et al, 2013;Patrucco et al, 2014).…”

“…Using an analogous protocol, 60-day-old AT 1 R transgenic mice and control animals from the same litters received SIL (400 mg/l) in acidified drinking water (pH 4.5) for 2 months. This dose of SIL was shown to be antifibrotic in an Ang II-stimulated model of cardiac hypertrophy (Patrucco et al, 2014) and yielded an average plasma concentration of 70 nM (Adamo et al, 2010). This concentration is well in the range to inhibit PDE5 (IC 50 , 10 nM).…”

“…Reportedly, AT 1 R transgenic mice develop a severe cardiac phenotype, i.e., progressive primary CM hypertrophy with secondary interstitial fibrosis even in the absence of Ang II (Yasuda et al, 2012) and high blood pressure (Paradis et al, 2000;Karnik and Unal, 2012). We tested whether SIL at a previously confirmed antifibrotic dose resulting in a free plasma concentration of ∼70 nM (Adamo et al, 2010;Patrucco et al, 2014) would interfere with amplified in vivo AT 1 R signaling in the aMHC-AT 1 R tg/1 mouse model. Our data indicate that SIL does not prevent cardiac remodeling induced by CM-specific AT 1 R overexpression, suggesting that other cell types are involved in the potentially favorable effects of this drug.…”