PDE5 is a cGMP specific phosphodiesterase that plays an important role in regulating cellular cGMP levels. The present study demonstrates that right ventricular PDE5 abundance is increased in failing human hearts compared with non-failing myocardium. Increased PDE5 expression was most apparent in failing hearts from patients with ischemic cardiomyopathy where right ventricular myocardium exhibited more than four-fold increases in PDE5 protein abundance. Localization of PDE5 via immunohistochemical staining demonstrated that increased expression was likely a result of increases in cardiac myocyte PDE5, with vascular smooth muscle PDE5 expression providing background levels in both NF and failing hearts. Among individuals with non-ischemic cardiomyopathy, degrees of PDE5 up-regulation in the RV seem to be dependent on the severity of RV dysfunction. Our studies showing differential responses to acute PDE5 inhibition in isolated RV trabeculae provides the first direct evidence that increased PDE5 expression in failing human myocardium may modulate RV contractility independent of preload or afterload.
By selecting samples from different disease groups and examining the expression of PDE5 in the RV, we obtained insights into factors regulating PDE5 expression in the human myocardium. Unlike previous human studies focusing only on non-ischemic cardiomyopathy 14,17,18
, our comparison of ischemic versus non-ischemic cardiomyopathy revealed significantly greater RV PDE5 expression in ICM. Moreover, the presence of variable degrees of RV dysfunction provided an opportunity to demonstrate that the severity of RV dysfunction affects the degree of RV PDE5 up-regulation among patients with DCM. As with previous studies 14
, immunohistochemical staining demonstrated that increased overall myocardial PDE5 abundance in failing hearts was likely due to increased cardiac myocyte PDE5 expression with relatively unchanged expression in vascular smooth muscle. Thus, our data is generally in agreement with the result of earlier studies, but reveals further potential factors that may contribute to the regulation of PDE5 expression during disease progression.
Taken together, intergroup comparisons indicate that the etiology and severity of RV cardiomyopathy affect PDE5 expression while LVAD support does not significantly alter RV PDE5 expression. Accordingly, it is reasonable to speculate that one or more of the many hypertrophic signaling pathways activated in the failing myocardium 24
directly or indirectly contribute to increased PDE5 expression in the failing RV. For example, recent studies by Mokni et al demonstrated that angiotensin II infusion induces increased PDE expression (including PDE5) during the early phases of myocardial hypertrophy 25
, while other studies have linked oxidative stress to increased myocardial PDE5 expression 18
Previously, no direct association between the up-regulation of PDE5 and contractility alteration in human tissues have been reported. In studies that examined PDE5 up-regulation in failing human myocardium, animal models were used to understand the impact on tissue functions 14,17,18
. Assessing impacts of the up-regulation on human tissue could, to a certain degree, verifies the relevance of the results from the animal studies, given the reported difference between human and animal in metabolizing c-GMP 26
. Our results reported here showed that PDE5 inhibitor, MY5445, acutely increases the contractility of muscle strips isolated from the failing hearts independent of effects on preload or afterload. Our finding that acute PDE5 inhibition increases contractility and prior studies indicating that PDE5 inhibition protects against cardiac hypertrophy in animal models 14,19,27,28
, support the possibility that increased PDE5 expression may exacerbate RV dysfunction and hypertrophy in the failing heart. Important caveats concerning this possibility relate to difference in time frame and compensatory responses in our studies versus clinical trials. For example, our data demonstrates functional actions of acute PDE5 inhibition during an interval of less than one hour while clinical trials examine responses over much longer intervals. With respect to compensatory responses, a strength of using isolated myocardial trabeculae is that intrinsic contractile responses to PDE5 can be assessed without potentially confounding changes in preload, afterload, perfusion or neurohormonal influences. In vivo, these influences may change and shape the overall myocardial response to PDE5 inhibition.
Together, our findings suggest that PDE5 inhibition in patients with pulmonary arterial hypertension may have both direct (via inotropy) and indirect (via reduced afterload) positive effects on right ventricular contractility. Such findings also suggest that up-regulated myocardial PDE5 expression may contribute to the progression of heart failure and support an emerging therapeutic role for PDE5 inhibitors for both right and left ventricular failure 19