PDE2 is cardioprotective in chronic heart failure

Abstract

Abstract Background Patients with chronic heart failure (HF) often develop life-threatening arrhythmia due to structural and electrophysiological cardiac remodelling. The chronic activation of the sympathetic nervous system is initially able to compensate the reduced myocardial contraction. Finally, long-term activation of the β-adrenergic pathway leads to deleterious activation of cAMP-dependent kinases and dysregulation of intracellular Ca2+ handling promoting HF progression and development of arrhythmia. Interestingly, phosphodiesterase 2 (PDE2), an enzyme to hydrolyze cAMP, is upregulated in human HF. Thus, PDE2 might reduce enhanced cAMP levels and pro-arrhythmic Ca2+ releases in HF. Purpose We investigated the effects of genetic PDE2 deletion on cardiac function, cellular contraction and arrhythmia occurrence in murine HF model. Methods HF was induced via high fat (60 %) diet (HFD) and the treatment with NO-synthase inhibitor L-NAME (0.5 g/l) for 5 weeks in cardiomyocyte-specific PDE2-knockout mice (KO) and control mice (WT). We characterized cardiac function by echocardiography, arrhythmia development by ECG-telemetry, cellular contraction by video-based analysis of sarcomere-shortening and cellular Ca2+ releases using Ca2+ imaging techniques. Results After 5 weeks HFD and L-NAME, mice gained weight, displayed increased blood pressure and reduced systolic and diastolic cardiac function. Interestingly, PDE2 KO showed reduced contractility and ejection fraction compared to WT mice after 5 weeks HF. On cellular level, the contraction of isolated cardiomyocytes slightly increased in HF indicating cardiac hypertrophy. However, the β-adrenergic stimulation with isoprenaline (ISO) enhanced cellular contraction only in non-failing WT mice, but was blunted in cells from failing WT hearts reflecting a desensitization of the β-adrenergic pathway. In contrast, the ISO-induced increase in cellular contraction was preserved in failing hearts from KO mice. Interestingly, PDE2 inhibition with BAY 60-7550 increased the ISO-induced cellular contraction in HF from WT, which was not observed in cells from non-failing mice. In HF, the expression of Ca2+ cycling proteins like phospholamban (PLB) were affected. Failing PDE2 KO mice showed higher phosphorylation levels of PLB compared to WT mice with HF. In diseased hearts, pro-arrhythmic triggers like spontaneous Ca2+ waves and Ca2+ sparks were increased. Importantly, diseased PDE2 KO mice developed more arrhythmia in-vivo upon arrhythmia provocation than WT animals. Conclusion Cardiac PDE2 deletion was detrimental in HF showing reduced cardiac function and higher number of arrhythmia. PDE2 stimulation might serve as potential therapeutical target in HF limiting the consequences of chronic β-adrenergic hyperactivation.