Abstract
BackgroundThe intracellular second messenger cGMP protects the heart under pathological conditions. We examined expression of phosphodiesterase 5 (PDE5), an enzyme that hydrolyzes cGMP, in human and mouse hearts subjected to sustained left ventricular (LV) pressure overload. We also determined the role of cardiac myocyte-specific PDE5 expression in adverse LV remodeling in mice after transverse aortic constriction (TAC).Methodology/Principal FindingsIn patients with severe aortic stenosis (AS) undergoing valve replacement, we detected greater myocardial PDE5 expression than in control hearts. We observed robust expression in scattered cardiac myocytes of those AS patients with higher LV filling pressures and BNP serum levels. Following TAC, we detected similar, focal PDE5 expression in cardiac myocytes of C57BL/6NTac mice exhibiting the most pronounced LV remodeling. To examine the effect of cell-specific PDE5 expression, we subjected transgenic mice with cardiac myocyte-specific PDE5 overexpression (PDE5-TG) to TAC. LV hypertrophy and fibrosis were similar as in WT, but PDE5-TG had increased cardiac dimensions, and decreased dP/dtmax and dP/dtmin with prolonged tau (P<0.05 for all). Greater cardiac dysfunction in PDE5-TG was associated with reduced myocardial cGMP and SERCA2 levels, and higher passive force in cardiac myocytes in vitro.Conclusions/SignificanceMyocardial PDE5 expression is increased in the hearts of humans and mice with chronic pressure overload. Increased cardiac myocyte-specific PDE5 expression is a molecular hallmark in hypertrophic hearts with contractile failure, and represents an important therapeutic target.
Highlights
Sustained left ventricular (LV) pressure overload, as in aortic stenosis (AS), causes pathological hypertrophy, reactivation of a fetal gene program, and maladaptive molecular alterations that initiate transition to heart failure [1]
In AS patients, phosphodiesterase 5 (PDE5) expression was markedly induced in scattered cardiac myocytes (Figure 1A and 1B)
In this study we report elevated myocardial PDE5 expression in patients with severe aortic stenosis undergoing aortic valve replacement (AVR), and in mice exposed to chronic pressure overload induced by transverse aortic constriction (TAC)
Summary
Sustained left ventricular (LV) pressure overload, as in aortic stenosis (AS), causes pathological hypertrophy, reactivation of a fetal gene program, and maladaptive molecular alterations that initiate transition to heart failure [1]. Accumulating evidence points to a cardioprotective role of the ubiquitous intracellular second messenger cyclic guanosine 3’, 5’-monophosphate (cGMP) in this pathological response [2]. PDE5 expression in the heart is low, but, in human right ventricular hypertrophy and advanced LV failure, PDE5 is increased in cardiac myocytes, suggesting that the enzyme has a role in the adaptation to increased stress [6,7,8]. In view of the wide expression of PDE1 in the cardiovascular system, including in cardiac myocytes, possible cross-reactivity is relevant [13]. We examined expression of phosphodiesterase 5 (PDE5), an enzyme that hydrolyzes cGMP, in human and mouse hearts subjected to sustained left ventricular (LV) pressure overload. We determined the role of cardiac myocyte-specific PDE5 expression in adverse LV remodeling in mice after transverse aortic constriction (TAC)
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