Role of Ca ²⁺ /Calmodulin-Stimulated Cyclic Nucleotide Phosphodiesterase 1 in Mediating Cardiomyocyte Hypertrophy

Abstract

Rationale: Cyclic nucleotide phosphodiesterases (PDEs) through the degradation of cGMP play critical roles in maintaining cardiomyocyte homeostasis. Ca 2؉ /calmodulin (CaM)-activated cGMP-hydrolyzing PDE1 family may play a pivotal role in balancing intracellular Ca 2؉ /CaM and cGMP signaling; however, its function in cardiomyocytes is unknown. Objective: Herein, we investigate the role of Ca 2؉ /CaM-stimulated PDE1 in regulating pathological cardiomyocyte hypertrophy in neonatal and adult rat ventricular myocytes and in the heart in vivo. Methods and Results: Inhibition of PDE1 activity using a PDE1-selective inhibitor, IC86340, or downregulation of PDE1A using siRNA prevented phenylephrine induced pathological myocyte hypertrophy and hypertrophic marker expression in neonatal and adult rat ventricular myocytes. Importantly, administration of the PDE1 inhibitor IC86340 attenuated cardiac hypertrophy induced by chronic isoproterenol infusion in vivo. Both PDE1A and PDE1C mRNA and protein were detected in human hearts; however, PDE1A expression was conserved in rodent hearts. Moreover, PDE1A expression was significantly upregulated in vivo in the heart and myocytes from various pathological hypertrophy animal models and in vitro in isolated neonatal and adult rat ventricular myocytes treated with neurohumoral stimuli such as angiotensin II (Ang II) and isoproterenol. Key Words: phosphodiesterase Ⅲ cGMP Ⅲ cardiomyocyte Ⅲ cardiac hypertrophy C a 2ϩ /calmodulin (CaM)-dependent signaling has been implicated in promoting pathological gene expression involved in hypertrophy and heart failure through the activation of Ca 2ϩ /CaM-dependent kinases, phosphatases, and ion channels. 1 Recently, a number of intrinsic negative regulators of cardiac growth have been identified which activate cGMPdependent signaling. 2 Stimulation of cGMP synthesis through genetic upregulation of natriuretic peptide receptor (guanylyl cyclase-A) prevents neurohumoral or pressure overload induced hypertrophy, 3 whereas disruption of cGMP synthesis results in enhanced hypertrophy and deteriorated cardiac function. 4 Likewise, chronic inhibition of cGMP metabolism by a cyclic nucleotide phosphodiesterase (PDE)5 inhibitor prevents and reverses pressure overload induced cardiac hypertrophy. 5 PDEs, by degrading cAMP and/or cGMP, regulate the amplitude, duration, and compartmentation of intracellular cyclic nucleotide signaling. PDEs constitute a superfamily of enzymes grouped into 11 broad families based on their distinct kinetic, regulatory, and inhibitory properties. PDE family members are also differentially expressed in various tissues and present within distinct subcellular domains. Together, these properties enable PDE enzymes to regulate the spatiotemporal, intracellular cAMP and cGMP gradients in response to various external stimuli. At least 5 PDE families, PDE1 to -5, have been reported in the heart, of which PDE1 and PDE5 are most likely responsible for cGMP hydrolysis. Logically, alteration of cGMP-hydrolyzing PDE expression/ activity...

Rare DNA copy number variants in cardiovascular malformations with extracardiac abnormalities

“…PDE1A, phosphodiesterase 1A, is calmodulin dependent, expressed in brain and heart 50 and has been shown to regulate cardiac hypertrophy in animal model. 51 Deletion on 13q32.3-q33 was observed in three individuals, two with septal defects and one with complex CVM phenotype. NALCN, a neuronal voltage-independent nonselective cation channel gene within this interval, is known to be expressed in heart.…”

PDE1C deficiency antagonizes pathological cardiac remodeling and dysfunction

“…Cardiac myocytes were separated from fibroblasts via gravity filtration and centrifugation. Myocyte hypertrophy was assessed as described previously, with modifications (13). Myocytes were cultured with the contractility inhibitor Blebbistatin, and hypertrophy was induced via treatment with ISO (10 μM) or Ang II (100 nM) for 72 h without changing medium.…”

“…PDE1 represents a major PDE activity in human myocardium (12), but its role in cardiac biology and disease remains elusive. Three distinct genes, PDE1A, -1B, and -1C, have been reported, with PDE1A and -1C expressed in the heart (13). PDE1A hydrolyzes cGMP with greater affinity than cAMP, whereas PDE1C hydrolyzes both similarly.…”

“…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.…”

Regulation and role of myocyte cyclic GMP-dependent protein kinase-1

“…Studies have also used tadalafil, which is more selective for PDE5. Last, whereas PDE1 inhibition seems to be antihypertrophic, this effect is cGK1-dependent and separable from a PDE5 inhibitory effect (i.e., they were additive) (5).…”