PDE1C deficiency antagonizes pathological cardiac remodeling and dysfunction

Abstract

Cyclic nucleotide phosphodiesterase 1C (PDE1C) represents a major phosphodiesterase activity in human myocardium, but its function in the heart remains unknown. Using genetic and pharmacological approaches, we studied the expression, regulation, function, and underlying mechanisms of PDE1C in the pathogenesis of cardiac remodeling and dysfunction. PDE1C expression is up-regulated in mouse and human failing hearts and is highly expressed in cardiac myocytes but not in fibroblasts. In adult mouse cardiac myocytes, PDE1C deficiency or inhibition attenuated myocyte death and apoptosis, which was largely dependent on cyclic AMP/PKA and PI3K/AKT signaling. PDE1C deficiency also attenuated cardiac myocyte hypertrophy in a PKA-dependent manner. Conditioned medium taken from PDE1C-deficient cardiac myocytes attenuated TGF-β-stimulated cardiac fibroblast activation through a mechanism involving the crosstalk between cardiac myocytes and fibroblasts. In vivo, cardiac remodeling and dysfunction induced by transverse aortic constriction, including myocardial hypertrophy, apoptosis, cardiac fibrosis, and loss of contractile function, were significantly attenuated in PDE1C-knockout mice relative to wild-type mice. These results indicate that PDE1C activation plays a causative role in pathological cardiac remodeling and dysfunction. Given the continued development of highly specific PDE1 inhibitors and the high expression level of PDE1C in the human heart, our findings could have considerable therapeutic significance.cyclic nucleotide | phosphodiesterase | cardiac remodeling | heart failure

Vinpocetine Attenuates Pathological Cardiac Remodeling by Inhibiting Cardiac Hypertrophy and Fibrosis

“…Among them, PDE1A and PDE1C but not PDE1B are expressed in the mouse heart [12]. Indeed, we found that Ang II infusion increased PDE1A and PDE1C expression (Online Resource 4a, b) and PDE1 activity (Online Resource 4c) in the heart, consistent with previously reported upregulation of PDE1A and PDE1C mRNA and/or protein in rodent and human hearts under pathological remodeling [12, 13, 17]. PDE1 family members are Ca 2+ /CaM-stimulated PDEs, and we have previously shown that PDE1 is responsible for Ang II-mediated reduction of cGMP in cardiomyocytes as assessed by using the PDE1-selective inhibitor IC86340 [12, 13].…”

“…Interestingly, the effects of vinpocetine on inhibiting cardiac fibroblast activation and matrix protein expression were also independent on Smad2/3 phosphorylation/activation (data not shown), which is consistent with the previous result from PDE1-selective inhibitor IC86340 [13]. Recently, we also reported the role of PDE1C deficiency in antagonizing pathological remodeling induced by thoracic aortic constriction (TAC) [17]. In the current study, we further showed that, when PDE1 activity was inhibited by the selective inhibitor IC86340, vinpocetine exhibited no additional effects on cardiomyocytes hypertrophy (Fig.…”

“…We have previously shown that both PDE1A and PDE1C are detected in the heart, and the expression of them was significantly upregulated in mouse hearts with pathological remodeling induced by thoracic aorta constriction and/or myocardial infarction, as well as human failing hearts [12, 13, 17]. Consistently, PDE1A and/or PDE1C expression was also up-regulated by Ang II (Supplemental Fig.…”

Maturation of human induced pluripotent stem cell-derived cardiomyocytes for modeling hypertrophic cardiomyopathy

“…In neonatal cardiomyocytes, agents such as the alpha-adrenergic receptor agonist phenylephrine (PE) induce a 50-100% in increase in cell area 21,22 , whereas the response in adult cardiomyocytes is typically only 10-30% 21,23,24 . Therefore, we investigated the response of hiPSC-CMs to PE.…”

Cardiac Cyclic Nucleotide Phosphodiesterases: Roles and Therapeutic Potential in Heart Failure

“…Phosphodiesterase 1C mRNA and protein are raised in failing mouse and human hearts [61]. Likewise, PDE1A protein expression is increased by AngII and the β-AR agonist isoprenaline (ISO) in isolated cardiomyocytes, as well as following pressure overload (i.e.…”