PDE2-mediated cAMP hydrolysis accelerates cardiac fibroblast to myofibroblast conversion and is antagonized by exogenous activation of cGMP signaling pathways

Abstract

Recent studies suggest that the signal molecules cAMP and cGMP have antifibrotic effects by negatively regulating pathways associated with fibroblast to myofibroblast (MyoCF) conversion. The phosphodiesterase 2 (PDE2) has the unique property to be stimulated by cGMP, which leads to a remarkable increase in cAMP hydrolysis and thus mediates a negative cross-talk between both pathways. PDE2 has been recently investigated in cardiomyocytes; here we specifically addressed its role in fibroblast conversion and cardiac fibrosis. PDE2 is abundantly expressed in both neonatal rat cardiac fibroblasts (CFs) and cardiomyocytes. The overexpression of PDE2 in CFs strongly reduced basal and isoprenaline-induced cAMP synthesis, and this decrease was sufficient to induce MyoCF conversion even in the absence of exogenous profibrotic stimuli. Functional stress-strain experiments with fibroblast-derived engineered connective tissue (ECT) demonstrated higher stiffness in ECTs overexpressing PDE2. In regard to cGMP, neither basal nor atrial natriuretic peptide-induced cGMP levels were affected by PDE2, whereas the response to nitric oxide donor sodium nitroprusside was slightly but significantly reduced. Interestingly, despite persistently depressed cAMP levels, both cGMP-elevating stimuli were able to completely prevent the PDE2-induced MyoCF phenotype, arguing for a double-tracked mechanism. In conclusion, PDE2 accelerates CF to MyoCF conversion, which leads to greater stiffness in ECTs. Atrial natriuretic peptide- and sodium nitroprusside-mediated cGMP synthesis completely reverses PDE2-induced fibroblast conversion. Thus PDE2 may augment cardiac remodeling, but this effect can also be overcome by enhanced cGMP. The redundant role of cAMP and cGMP as antifibrotic meditators may be viewed as a protective mechanism in heart failure.

Effects of Atrial Natriuretic Peptide on Rat Ventricular Fibroblasts During Differentiation Into Myofibroblasts

“…Furthermore, scanning and quantifying cGMP dependent PDE isoenzymes was performed on 12 days serum induced myofibroblasts and reveal 5 different transcript expression. Expression of these specific PDEs seems to have a central role in modulating cGMP (Qvigstad et al 2009, Vettel et al 2014, thus modulating the ANP/NPRA system. Lu et al (2013) quantified PDEs in TGF-β induced cardiac myofibroblasts obtained from Sprague-Dawley rats, and their studies have showed that cAMP can prevent the CFs to myofibroblasts transformation and that increased cAMP levels can reverse the profibrotic myofibroblastic phenotype.…”

New Insights in (Inter)Cellular Mechanisms by Heart Failure with Preserved Ejection Fraction

“…Secondly, endothelial dysfunction contributes to cardiac fibrosis via the reduced bioavailability of NO, known to exert direct anti-fibrotic effects involving the cyclic guanosine monophosphate (cGMP) pathway [41, 42]. Vettel et al [42] recently demonstrated that the cGMP/cyclic adenosine monophosphate (cAMP)-hydrolyzing phosphodiesterase (PDE) 2, which is upregulated in human failing hearts [43], leads to a decrease in cAMP levels in cardiac fibroblasts and accelerates the conversion of fibroblasts to myofibroblasts.…”

“…Vettel et al [42] recently demonstrated that the cGMP/cyclic adenosine monophosphate (cAMP)-hydrolyzing phosphodiesterase (PDE) 2, which is upregulated in human failing hearts [43], leads to a decrease in cAMP levels in cardiac fibroblasts and accelerates the conversion of fibroblasts to myofibroblasts. Exogenous activation of cGMP via atrial natriuretic peptide (ANP) or NO was able to bypass the PDE2-mediated degradation of cAMP and reversed the differentiation of fibroblasts into myofibroblasts.…”

Emerging Role of Phosphodiesterase 2A in Hypertension

“…2 In engineered connective tissue, phosphodiesterase 2 enhances the conversion of fibroblasts to myofibroblasts, thereby increasing tissue stiffness. 3 Finally, phosphodiesterase 2 inhibitors induce relaxation of pulmonary arteries and inhibit proliferation of pulmonary arterial smooth muscle cells, indicating that phosphodiesterase 2 inhibitors may constitute an effective strategy for treatment of pulmonary hypertension. 4 On this background, published in this issue of Hypertension, a study by Li et al 5 adds a new facet to the emerging roles of phosphodiesterase 2 in the pathophysiology of cardiovascular diseases.…”

“…1 Moreover, in the study of Li et al 5 on sympathetic neurons, phosphodiesterase 2A exhibited the properties of a cGMP-specific phosphodiesterase (Figure), but in other systems phosphodiesterase 2 regulates both cAMP and cGMP. 3,4 This may reflect differential compartmentalization of proteins involved in cAMP and cGMP signaling.…”