Cyclic nucleotide phosphodiesterase 1A: a key regulator of cardiac fibroblast activation and extracellular matrix remodeling in the heart

Abstract

Cardiac fibroblasts become activated and differentiate to smooth muscle-like myofibroblasts in response to hypertension and myocardial infarction (MI), resulting in extracellular matrix (ECM) remodeling, scar formation and impaired cardiac function. cAMP and cGMP-dependent signaling have been implicated in cardiac fibroblast activation and ECM synthesis. Dysregulation of cyclic nucleotide phosphodiesterase (PDE) activity/expression is also associated with various diseases and several PDE inhibitors are currently available or in development for treating these pathological conditions. The objective of this study is to define and characterize the specific PDE isoform that is altered during cardiac fibroblast activation and functionally important for regulating myofibroblast activation and ECM synthesis. We have found that Ca2+/calmodulin-stimulated PDE1A isoform is specifically induced in activated cardiac myofibroblasts stimulated by Ang II and TGF-β in vitro as well as in vivo within fibrotic regions of mouse, rat, and human diseased hearts. Inhibition of PDE1A function via PDE1-selective inhibitor or PDE1A shRNA significantly reduced Ang II or TGF-β-induced myofibroblast activation, ECM synthesis, and pro-fibrotic gene expression in rat cardiac fibroblasts. Moreover, the PDE1 inhibitor attenuated isoproterenol-induced interstitial fibrosis in mice. Mechanistic studies revealed that PDE1A modulates unique pools of cAMP and cGMP, predominantly in perinuclear and nuclear regions of cardiac fibroblasts. Further, both cAMP-Epac-Rap1 and cGMP-PKG signaling was involved in PDE1A-mediated regulation of collagen synthesis. These results suggest that induction of PDE1A plays a critical role in cardiac fibroblast activation and cardiac fibrosis, and targeting PDE1A may lead to regression of the adverse cardiac remodeling associated with various cardiac diseases.

PDE1C deficiency antagonizes pathological cardiac remodeling and dysfunction

“…Thus, PDE1C may represent a compelling therapeutic target, because inhibition of this enzyme may prevent diverse aspects of pathological cardiac remodeling in multiple cell types. In addition, we have shown previously that the PDE1A isoform inhibition attenuates cardiac myocyte hypertrophy (13) and fibroblast activation (14) largely through a cGMP-dependent mechanism. Thus, our previous and current findings may have considerable therapeutic impact, because they may lead to the development of novel therapeutic strategies using PDE1 inhibitors to combat pathological cardiac remodeling and dysfunction.…”

“…PDE1A hydrolyzes cGMP with greater affinity than cAMP, whereas PDE1C hydrolyzes both similarly. We previously demonstrated that treatment with a pan-PDE1 inhibitor significantly reduced isoproterenol (ISO)-induced cardiac hypertrophy and fibrosis (13,14), but these studies were unable to delineate the contributions of individual PDE1 isozymes to this effect. Our preliminary studies indicated that PDE1C expression is increased in failing human and mouse hearts; therefore we investigated the regulation and function of PDE1C in pathological cardiac Significance Heart failure is the leading global cause of death; therefore developing a greater understanding of disease etiology and identifying novel therapeutic targets is critical.…”

Increase in Cellular Cyclic AMP Concentrations Reverses the Profibrogenic Phenotype of Cardiac Myofibroblasts: A Novel Therapeutic Approach for Cardiac Fibrosis

“…1). Since increased cellular concentrations of cAMP can blunt the transformation of CFs to myofibroblasts (Swaney et al, 2005;Yokoyama et al, 2008;Miller et al, 2011), we infer that the decrease in the ability of myofibroblasts to generate cAMP and cAMP Reverses the Cardiac Myofibroblast Phenotype increased ability to hydrolyze cAMP contribute to the myofibroblastic phenotype.…”

“…Previous data have indicated that incubation of CFs with agents that increase cellular cAMP levels when cells are also incubated with TGF-b1 blocks the conversion of CFs to myofibroblasts (Swaney et al, 2005;Yokoyama et al, 2008;Miller et al, 2011). To test whether raising cAMP levels in myofibroblasts can reverse an already-developed profibrotic state, we treated myofibroblasts (CFs that were incubated with TGF-b1 for 4 or 6 days) (Fig.…”

“…One potential mediator is the second messenger cyclic AMP. Activation of cAMP-dependent processes is known to inhibit CF-to-myofibroblast conversion (Swaney et al, 2005;Miller et al, 2011) and overexpression of adenylyl cyclase (AC) and activation of Gs-coupled G protein-coupled receptors (GPCRs), which stimulate cAMP synthesis and decrease collagen synthesis and a-SMA expression in CFs (Davaille et al, 2000;Heusinger-Ribeiro et al, 2001;Swaney et al, 2005;Yokoyama et al, 2008;Schiller et al, 2010). However, the contribution of cAMP to maintain, and potentially to reverse, the profibrotic state is not known.…”