Cardiac Hypertrophy Is Inhibited by a Local Pool of cAMP Regulated by Phosphodiesterase 2

Abstract

Rationale : Chronic elevation of 3′-5′-cyclic adenosine monophosphate (cAMP) levels has been associated with cardiac remodeling and cardiac hypertrophy. However, enhancement of particular aspects of cAMP/protein kinase A signaling seems to be beneficial for the failing heart. cAMP is a pleiotropic second messenger with the ability to generate multiple functional outcomes in response to different extracellular stimuli with strict fidelity, a feature that relies on the spatial segregation of the cAMP pathway components in signaling microdomains. Objective : How individual cAMP microdomains affect cardiac pathophysiology remains largely to be established. The cAMP-degrading enzymes phosphodiesterases (PDEs) play a key role in shaping local changes in cAMP. Here we investigated the effect of specific inhibition of selected PDEs on cardiac myocyte hypertrophic growth. Methods and Results : Using pharmacological and genetic manipulation of PDE activity, we found that the rise in cAMP resulting from inhibition of PDE3 and PDE4 induces hypertrophy, whereas increasing cAMP levels via PDE2 inhibition is antihypertrophic. By real-time imaging of cAMP levels in intact myocytes and selective displacement of protein kinase A isoforms, we demonstrate that the antihypertrophic effect of PDE2 inhibition involves the generation of a local pool of cAMP and activation of a protein kinase A type II subset, leading to phosphorylation of the nuclear factor of activated T cells. Conclusions : Different cAMP pools have opposing effects on cardiac myocyte cell size. PDE2 emerges as a novel key regulator of cardiac hypertrophy in vitro and in vivo, and its inhibition may have therapeutic applications.

Phosphodiesterase 2: anti-adrenergic friend or hypertrophic foe in heart disease?

“…Moreover, when they normalize their data, it looks similar to ours (online Fig. XII of Zoccarato et al 2015). Consequently, they imply that we may have misinterpreted our data.…”

“…III of Zoccarato et al 2015) and does not attenuate hypertrophy induced by norepinephrine (online Fig. VII of Zoccarato et al 2015). Since in our original publication, we normalized both the control virus and the PDE2A overexpressing virus under control conditions to 100 %, Zoccarato et al suggest that our results could have been obfuscated by the normalization.…”

“…Zoccarato et al (2015) suggest in a number of well-designed experiments on isolated cardiomyocytes as well as in vivo that PDE2A regulates a local cAMP pool that acts anti-hypertrophically by activating PKA II, leading to phosphorylation of nuclear factors of activated T cells (NFAT) and reducing their nuclear localization which reduces the expression of hypertrophic genes.…”

“…7 of Mehel et al 2013) in adult rat ventricular myocytes (ARVMs), while Zoccarato et al suggest that PDE2A overexpression alone leads to hypertrophy in ARVMs (online Fig. III of Zoccarato et al 2015) and does not attenuate hypertrophy induced by norepinephrine (online Fig. VII of Zoccarato et al 2015).…”

Suppressive Effects of Glucose-Dependent Insulinotropic Polypeptide on Cardiac Hypertrophy and Fibrosis in Angiotensin II-Infused Mouse Models

“…4 In contrast, cardiac hypertrophy can be prevented by the enhancement of cAMP/PKA signaling via the inhibition of cAMP-degrading enzyme phosphodiesterase-2. 5 Recent studies have shown that hormonespecific actions result from different cAMP pools and PKA localization within cardiomyocytes. 6,7 These findings indicate 2 possibilities; that activation of GIP signaling could act protective against cardiac hypertrophy, or, on the contrary, lead to hypertrophic changes in the heart.…”