Abstract
Pathological cardiac hypertrophy and dysfunction is a response to various stress stimuli and can result in reduced cardiac output and heart failure. Cyclic nucleotide signaling regulates several cardiac functions including contractility, remodeling, and fibrosis. Cyclic nucleotide phosphodiesterases (PDEs), by catalyzing the hydrolysis of cyclic nucleotides, are critical in the homeostasis of intracellular cyclic nucleotide signaling and hold great therapeutic potential as drug targets. Recent studies have revealed that the inhibition of the PDE family member PDE1 plays a protective role in pathological cardiac remodeling and dysfunction by the modulation of distinct cyclic nucleotide signaling pathways. This review summarizes recent key findings regarding the roles of PDE1 in the cardiac system that can lead to a better understanding of its therapeutic potential.
Highlights
Heart failure, the inability of the heart to provide sufficient blood to the body, is a leading cause of death in the United States
PDE1C is expressed in cardiac myocytes but not fibroblasts [49]
PDE1A and PDE1C both regulate cardiac myocyte hypertrophy induced by pathological stimuli such as Ang II, but via distinct signaling pathways: PDE1A acts through cGMP/PKG while PDE1C acts through cAMP/protein kinase A (PKA) [45,49]
Summary
The inability of the heart to provide sufficient blood to the body, is a leading cause of death in the United States. Heart failure is associated with significant myocardial deterioration, including pathological hypertrophy, fibrosis, and cell death, as well as contractile dysfunction and ventricular arrhythmia [1]. Identifying novel molecular targets involved in pathological cardiac remodeling and dysfunction is crucial. Cyclic nucleotide signaling is important in numerous biological functions and pathological processes in the cardiovascular system, ranging from short-term muscle contraction/relaxation to long-term cell growth/survival and structural remodeling [2]. Phosphodiesterases (PDEs), by catalyzing the hydrolysis of cyclic nucleotides, play important roles in the regulation of intracellular cyclic nucleotide amplitude, duration, and compartmentalization [3]. Alterations in PDE expression and activity are responsible for disruptions in cyclic nucleotide homeostasis, contributing to disease progression [3]. We give an overview of the role and therapeutic potential of PDE1 regulation in pathological cardiac remodeling and dysfunction
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