Cardiac cyclic nucleotide phosphodiesterases: function, regulation, and therapeutic prospects

Abstract

The second messengers cAMP and cGMP exist in multiple discrete compartments and regulate a variety of biological processes in the heart. The cyclic nucleotide phosphodiesterases, by catalyzing the hydrolysis of cAMP and cGMP, play crucial roles in controlling the amplitude, duration, and compartmentalization of cyclic nucleotide signaling. Over 60 phosphodiesterase isoforms, grouped into 11 families, have been discovered to date. In the heart, both cAMP- and cGMP-hydrolyzing phosphodiesterases play important roles in physiology and pathology. At least 7 of the 11 phosphodiesterase family members appear to be expressed in the myocardium, and evidence supports phosphodiesterase involvement in regulation of many processes important for normal cardiac function including pacemaking and contractility, as well as many pathological processes including remodeling and myocyte apoptosis. Pharmacological inhibitors for a number of phosphodiesterase families have also been used clinically or preclinically to treat several types of cardiovascular disease. In addition, phosphodiesterase inhibitors are also being considered for treatment of many forms of disease outside the cardiovascular system, raising the possibility of cardiovascular side effects of such agents. This review will discuss the roles of phosphodiesterases in the heart, in terms of expression patterns, regulation, and involvement in physiological and pathological functions. Additionally, the cardiac effects of various phosphodiesterase inhibitors, both potentially beneficial and detrimental, will be discussed.

Fig. 1

cAMP-mediated signaling pathways in the left ventricular cardiomyocyte. When an external stimulus, particularly a β-adrenergic agonist, binds to a β-AR, AC becomes activated, resulting in the production of cAMP. Cellular cAMP primarily serves to activate PKA. PKA phosphorylates a number of targets in the myocyte. Phosphorylation of targets involving Ca ²⁺ cycling increases myocyte contractility. Phosphorylation of transcription factors/regulators regulates gene expression, promoting myocyte hypertrophic growth and apoptosis. By degrading cAMP, a number of PDEs are involved in regulation of these processes, often in different subcellular compartments. PDE3, PDE4 and PDE8 are all implicated in regulating myocyte excitation-contraction coupling via modulation of LTCC, RyR2 and PLB/SERCA2, and so are particularly important in modulating the contractile response. By negatively regulating ICER in a PKA-dependent manner, PDE3 is also antiapoptotic. PDE2 appears to be most important in cGMP-mediated modulation of cAMP levels, while the role of PDE1 in regulating myocyte cAMP is less well characterized.

Fig. 2

cGMP-mediated signaling pathways in the left ventricular cardiomyocyte. cGMP can be produced by activation of either sGC via NOS/NO, or pGC via natriuretic peptides (ANP/BNP/CNP). cGMP produced by the 2 pathways appears to be compartmentalized into different regions of the myocyte. cGMP activates PKG, which has a number of cellular effects. Via PKG-mediated phosphorylation of LTCCs, PKG reduces myocyte contractility. PKG also inhibits a number of pro-hypertrophic mediators (such as Cn, NFAT, MEK/ERK1/2) in the myocyte, primarily through activation of RGS2, which blunts both G_αs and G_αq signaling. Cardiac cGMP levels are regulated primarily by PDE1 and PDE5, and inhibition of either of these enzymes appears to attenuate cardiac hypertrophy, and in the case of PDE5, also contractility. Via activation of PDE2, cGMP also modulates contractile functions in a species dependent manner. Note that these diagrams are based on observations in left ventricular myocytes, and some signaling pathways will be altered when looking at myocytes from other regions of the heart. AC: adenylyl cyclase; ANP: atrial natriuretic peptide; AT1R: angiotensin II type 1 receptor; β-AR: beta adrenergic receptor; BNP: brain natriuretic peptide; Cn: calcineurin; CNP: C-type natriuretic peptide; ERK1/2: extracellular signal-regulated kinase ½; G_αq: heterotrimeric G protein, G_αq class, alpha subunit; G_αs: heterotrimeric G protein, G_αs class, alpha subunit; ICER: inducible cAMP early repressor; LTCC: L-type Ca ²⁺ channel; MEK: mitogen activated ERK kinase; NFAT: nuclear factor of activated T-cells; NO: nitric oxide; NOS: NO synthase; pGC: particulate quanylyl cyclase; PKA: protein kinase A; PKG: protein kinase G; PLB: phospholamban; RGS2: RyR2: the cardiac ryanodine receptor; SERCA2: the cardiac SR Ca ²⁺ -release channel; sGC: soluble guanylyl cyclase; SR: sarcoplasmic reticulum.