Cardiac Phosphodiesterases and Their Modulation for Treating Heart Disease

Abstract

An important hallmark of cardiac failure is abnormal second messenger signaling due to impaired synthesis and catabolism of adenosine 3’,5’-cyclic monophosphate (cAMP) and cyclic guanosine 3’,5’-cyclic monophosphate (cGMP). Their dysregulation, altered intracellular targeting, and blunted responsiveness to stimulating pathways all contribute to pathological remodeling, muscle dysfunction, reduced cell survival and metabolism, and other abnormalities. Therapeutic enhancement of either cyclic nucleotide can be achieved by stimulating their synthesis and/or by suppressing members of the family of cyclic nucleotide phosphodiesterases (PDEs). The heart expresses seven of the eleven major PDE sub-types - PDE1, 2, 3, 4, 5, 8, and 9. Their differential control over cAMP and cGMP signaling in various cell types, including cardiomyocytes, provides intriguing therapeutic opportunities to counter heart disease. This review examines the roles of these PDEs in the failing and hypertrophied heart, and summarizes experimental and clinical data that has explored the utility of targeted PDE inhibition.

PDE5 inhibitors – pharmacology and clinical applications 20 years after sildenafil discovery

“…NOS3 is mostly found in coronary vascular and endocardial endothelial cells and, to a lesser extent, in cardiac myocytes, whereas NOS1 is predominantly localized to the sarcoplasmic reticulum. In the myocardium, constitutive NO production affects the function and phosphorylation state of several proteins that are involved in excitation‐contraction coupling, for example, the L‐type Ca 2+ channel, troponin I and phospholamban, and inhibits both oxygen consumption and β‐adrenoceptor mediated inotropy; abnormal NOS signalling plays a key role in many cardiac disorders (Carnicer et al, ; Kim and Kass, ). An important hallmark of cardiac failure is abnormal second messenger signalling due to impaired synthesis and catabolism of cAMP and cGMP.…”

“…The regulation of cardiac functions by endogenous NO has been suggested to be dependent on the distinct subcellular locations of nNOS and eNOS, through vascular‐dependent and vascular‐independent effects (Massion and Balligand, ). The heart expresses seven of the 11 major PDE sub‐types – PDE1, 2, 3, 4, 5, 8 and 9 (Kim and Kass, ) – and their different effects on cAMP and cGMP signalling in various cell types, including cardiomyocytes, provides intriguing therapeutic opportunities to counter heart disease. An abundant expression of PDE5 has been demonstrated in isolated canine or murine ventricular cardiomyocytes (Das et al, ), and PDE5 is highly expressed in both experimental and human heart disease.…”

“…An abundant expression of PDE5 has been demonstrated in isolated canine or murine ventricular cardiomyocytes (Das et al, ), and PDE5 is highly expressed in both experimental and human heart disease. There should thus be possibilities to influence cardiac function by PDE5 inhibition, and there is currently a tremendous interest in identifying new clinical uses of PDE5 inhibitors for treatment of a variety of cardiovascular diseases (Kim and Kass, ; Sevil Korkmaz‐Icöz et al, ).…”

HFpEF, a Disease of the Vasculature: A Closer Look at the Other Half

“…24 Phosphodiesterases (PDEs) hydrolyze cGMP, and 7 isoforms are thought to be expressed in the heart. 20 Three PDEs (PDE5, PDE6, and PDE9) are specific for cGMP; PDE6 is involved in photoreceptor signaling 25 and not expressed in cardiomyocytes. 26 The expression of PDE5 has been proposed to increase in heart failure and is thought to be associated with increased remodeling.…”

“…26 The expression of PDE5 has been proposed to increase in heart failure and is thought to be associated with increased remodeling. 20 Several studies 24,27,28 used PDE overexpression and knockdown mouse lines to exhibit that PDE5A inhibition suppressed cellular and molecular remodeling while improving cardiac function in states of chronic pressure overload. The inhibition of PDE5A was also noted to reverse preexisting hypertrophy while improving function.…”