Oxidative Stress Regulates Left Ventricular PDE5 Expression in the Failing Heart

Abstract

Background-Phosphodiesterase type 5 (PDE5) inhibition has been shown to exert profound beneficial effects in the failing heart, suggesting a significant role for PDE5 in the development of congestive heart failure (CHF). The purpose of this study is to test the hypothesis that oxidative stress causes increased PDE5 expression in cardiac myocytes and that increased PDE5 contributes to the development of CHF. Methods and Results-Myocardial PDE5 expression and cellular distribution were determined in left ventricular samples from patients with end-stage CHF and normal donors and from mice after transverse aortic constriction (TAC)-induced CHF. Compared with donor human hearts, myocardial PDE5 protein was increased Ϸ4.5-fold in CHF samples, and the increase of myocardial PDE5 expression was significantly correlated with myocardial oxidative stress markers 3Ј-nitrotyrosine or 4-hydroxynonenal expression (PϽ0.05). Histological examination demonstrated that PDE5 was mainly expressed in vascular smooth muscle in normal donor hearts, but its expression was increased in both cardiac myocytes and vascular smooth muscle of CHF hearts. Myocardial PDE5 protein content and activity also increased in mice after TAC-induced CHF (PϽ0.05). When the superoxide dismutase (SOD) mimetic M40401 was administered to attenuate oxidative stress, the increased PDE5 protein and activity caused by TAC was blunted, and the hearts were protected against left ventricular hypertrophy and CHF. Conversely, increased myocardial oxidative stress in superoxide dismutase 3 knockout mice caused a greater increase of PDE5 expression and CHF after TAC. In addition, administration of sildenafil to inhibit PDE5 attenuated TAC-induced myocardial oxidative stress, PDE5 expression, and CHF. Conclusions-Myocardial oxidative stress increases PDE5 expression in the failing heart. Reducing oxidative stress by treatment with M40401 attenuated cardiomyocyte PDE5 expression. This and selective inhibition of PDE5 protected the heart against pressure overload-induced left ventricular hypertrophy and CHF. (Circulation. 2010;121:1474-1483.)Key Words: heart failure Ⅲ oxidative stress Ⅲ cyclic nucleotide phosphodiesterases, type 5 C ongestive heart failure (CHF) is the leading cause of mortality in developed countries and continues to increase in prevalence. Phosphodiesterase type 5 (PDE5) selectively hydrolyzes cyclic 3Ј,5Ј-guanosine monophosphate (cGMP), and selective inhibition of PDE5 can increase cGMP bioavailability. It is generally believed that PDE5 is not present in normal cardiac myocytes, so that selective PDE5 inhibition has no direct inotropic effect in normal hearts. 1 However, recent work by Kass et al demonstrated that selective inhibition of PDE5 with sildenafil markedly attenuated the left ventricular (LV) hypertrophy and dysfunction produced by chronic pressure overload secondary to transverse aortic constriction (TAC) in mice. 2 Thus PDE5 inhibition has also been reported to attenuate myocardial infarctinduced LV remodeling 3 and LV hypertrophy produc...

Low Myocardial Protein Kinase G Activity in Heart Failure With Preserved Ejection Fraction

“…Upregulated PDE5A expression was previously observed in remodeled human myocardial tissue procured at cardiac surgery from hypertrophied right ventricles of congenital cardiac malformations 17 or at cardiac transplantation from explanted dilated or ischemic cardiomyopathic hearts. 18,19 Although PDE5A and sGC enzyme activities were not directly measured in the present study, the lower PKG activity and cGMP concentration in HFPEF than in AS or HFREF cannot be ascribed to higher expression of PDE5A nor to lower expression of sGC or proBNP-108. They therefore probably derived from lower myocardial NO bioavailability because of higher nitrosative/oxidative stress, which is known to directly impair NO-cGMP-PKG signaling.…”

Targeting phosphodiesterase 5 as a therapeutic option against myocardial ischaemia/reperfusion injury and for treating heart failure

“…Cardiac PDE5 expression was reported to be up-regulated in hypertrophic, dilated and ischaemic cardiomyopathy (Nagendran et al, 2007;Pokreisz et al, 2009;Vandeput et al, 2009) and in conditions such as congestive heart failure (HF) (Lu et al, 2010). Therefore, in certain disorders, the pharmacological inhibition of PDE5 could significantly increase intracellular cGMP levels in the myocardium.…”

“…It has been shown that oxidative stress increases the expression of PDE5 in the cardiomyocytes of failing hearts (Lu et al, 2010) and sildenafil attenuated oxidative stress by inhibiting free radical formation and by facilitating antioxidant redox systems (Bivalacqua et al, 2009;Perk et al, 2008). One of the mechanisms of action of PDE inhibitors might be to reduce oxidative stress levels, as PDE levels are up-regulated in conditions such as pulmonary hypertension, chronic HF and right ventricular hypertrophy (Corbin et al, 2005;Forfia et al, 2007;Nagendran et al, 2007) and oxidative stress mediates the dysfunctional NO-cGMP-PKG signalling in cardiovascular disease.…”

Cyclic GMP-Dependent Signaling in Cardiac Myocytes

“…1 The most recent study revealed that PDE5 represents ~20% of total cGMP-esterase activity in human cardiac myocytes, 16 though there still remains some debate. 18 PDE5 expression is upregulated in the diseased heart 22-25 via an oxidant stress-dependent mechanism, 26 and is activated by cGMP binding to the GAF domain and by PKG phosphorylation at Ser 92. 15 A PDE5 inhibitor such as sildenafil occupies its catalytic site as a false substrate to increase cGMP and activate PKG, leading to enhanced activity of the enzyme, and thus the inhibitor's efficacy.…”