RESEARCH ARTICLE The Emperor's New Clothes: PDE5 and the

Phosphodiesterase-5 (PDE5) is highly expressed in the pulmonary vasculature, but its ex-pression in the myocardium is controversial. Cyclic guanosine monophosphate (cGMP) acti-vates protein kinase G (PKG), which has been hypothesized to blunt cardiac hypertrophy and negative remodeling in heart failure. Although PDE5 has been suggested to play a significant role in the breakdown of cGMP in cardiomyocytes and hence PKG regulation in the myocardi-um, the RELAX trial, which tested effect of PDE5 inhibition on exercise capacity in patients with heart failure with preserved ejection fraction (HFpEF) failed to show a beneficial effect. These results highlight the controversy regarding the role and expression of PDE5 in the healthy and failing heart. This study used one- and two-dimensional electrophoresis and Western blotting to examine PDE5 expression in mouse (before and after trans-aortic con-striction), dog (control and HFpEF) as well as human (healthy and failing) heart. We were un-able to detect PDE5 in any cardiac tissue lysate, whereas PDE5 was present in the murine and bovine lung samples used as positive controls. These results indicate that if PDE5 is ex-pressed in cardiac tissue, it is present in very low quantities, as PDE5 was not detected in ei-ther humans or any model of heart failure examined. Therefore in cardiac muscle, it is unlikely that PDE5 is involved the regulation of cGMP-PKG signaling, and hence PDE5 does not rep-resent a suitable drug target for the treatment of cardiac hypertrophy. These results highlight the importance of rigorous investigation prior to clinical trial design