Background Ventricular expression of phosphodiesterase-5 (PDE5), an enzyme responsible for cGMP catabolism, is increased in human right ventricular hypertrophy, but its role in left ventricular (LV) failure remains incompletely understood. We therefore measured LV PDE5 expression in patients with advanced systolic heart failure and characterized LV remodeling after myocardial infarction (MI) in transgenic mice with cardiomyocyte-specific over-expression of PDE5 (PDE5-TG). Methods and Results Immunoblot and immunohistochemistry techniques revealed that PDE5 expression was greater in explanted LVs from patients with dilated and ischemic cardiomyopathy than in control hearts. To evaluate the impact of increased ventricular PDE5 levels on cardiac function, PDE5-TG mice were generated. Confocal and immunoelectron microscopy revealed increased PDE5 expression in cardiomyocytes predominantly localized to Z-bands. At baseline, myocardial cGMP levels, cell shortening and calcium handling in isolated cardiomyocytes, and LV hemodynamic measurements were similar in PDE5-TG and wild-type littermates (WT). Ten days after MI, LV cGMP levels increased to a greater extent in WT than PDE5-TG (P<0.05). Ten weeks after MI, LV end-systolic and -diastolic volumes were larger in PDE5-TG than in WT (57±5 vs 39±4 and 65±6 vs 48±4 µL, respectively, P<0.01 for both). LV systolic and diastolic dysfunction was more marked in PDE5-TG than WT associated with enhanced hypertrophy and reduced contractile function in isolated cardiomyocytes from remote myocardium. Conclusions Increased PDE5 expression predisposes mice to adverse LV remodeling after MI. Increased myocardial PDE5 expression in patients with advanced cardiomyopathy may contribute to the development of heart failure and represents an important therapeutic target.

Our findings highlight a regulatory role for ECs in FA transfer to the heart parenchyma and unveil 2 of its intrinsic regulators. Our insights could be used to develop new strategies based on endothelial Meox2/Tcf15 targeting to modulate FA transfer to the heart and remedy cardiac dysfunction resulting from altered energy substrate usage.

Infusion of late-outgrowth EPCs after AMI improves myocardial infarction remodeling via enhanced neovascularization but does not mediate cardiomyogenesis. Endothelial progenitor cell transfer might hold promise for heart failure prevention via pro-angiogenic or paracrine matrix-modulating effects.