Therapeutic Implications for PDE2 and cGMP/cAMP Mediated Crosstalk in Cardiovascular Diseases

Abstract

Phosphodiesterases (PDEs) are the principal superfamily of enzymes responsible for degrading the secondary messengers 3’,5’-cyclic nucleotides cAMP and cGMP. Their refined subcellular localization and substrate specificity contribute to finely regulate cAMP/cGMP gradients in various cellular microdomains. Redistribution of multiple signal compartmentalization components is often perceived under pathological conditions. Thereby PDEs have long been pursued as therapeutic targets in diverse disease conditions including neurological, metabolic, cancer and autoimmune disorders in addition to numerous cardiovascular diseases. PDE2 is a unique member of the broad family of PDEs. In addition to its capability to hydrolyze both cAMP and cGMP, PDE2 is the sole isoform that may be allosterically activated by cGMP increasing its cAMP hydrolyzing activity. Within the cardiovascular system, PDE2 serves as an integral regulator for the crosstalk between cAMP/cGMP pathways and thereby may couple chronically adverse augmented cAMP signalling with cardioprotective cGMP signalling. This review provides a comprehensive overview of PDE2 regulatory functions in multiple cellular components within the cardiovascular system and also within various subcellular microdomains. Implications for PDE2 mediated crosstalk mechanisms in diverse cardiovascular pathologies are discussed highlighting the prospective use of PDE2 as a potential therapeutic target in cardiovascular disorders.

Cellular Mechanisms of the Anti-Arrhythmic Effect of Cardiac PDE2 Overexpression

“…Among the family of cardiac PDEs, phosphodiesterase 2 (PDE2) has the unique property to be stimulated by cGMP via its GAF domains to primarily hydrolyze cAMP [ 18 ]. Thus, PDE2 can mediate a negative crosstalk between cGMP and cAMP signaling pathways [ 19 ]. The enzyme exists in three isoforms PDE2A1, 2, and 3, which are all generated by alternative exon splicing [ 19 , 20 ].…”

“…Thus, PDE2 can mediate a negative crosstalk between cGMP and cAMP signaling pathways [ 19 ]. The enzyme exists in three isoforms PDE2A1, 2, and 3, which are all generated by alternative exon splicing [ 19 , 20 ]. PDE2 isoforms are localized within the cytoplasm (mainly PDE2A1) or the membrane fractions comprising the plasma and nuclear membrane, sarcoplasmic reticulum, and the Golgi body (mostly PDE2A3) [ 21 , 22 ].…”

cGMP and mitochondrial K+ channels—Compartmentalized but closely connected in cardioprotection

“…While PDE5 and PDE9 are selective for cGMP, PDE1, PDE2, and PDE3 are dual substrate PDEs that catabolize cAMP as well. Interestingly, the activity of PDE2 is accelerated by cGMP binding to regulatory domains of this isoenzyme allowing this enzyme to establish an intensive crosstalk between cGMP and cAMP signals (Sadek, Cachorro, El-Armouche & Kammerer, 2020). Through competitive binding at the catalytic site of PDE3, cGMP interferes with PDE3-driven cAMP hydrolysis, yielding another mechanism of crosstalk between the two second messenger pathways (Figure 1d).…”

Cardiac Myofibroblast and Fibrosis

“…There are PDEs that degrade both cAMP and cGMP. PDE2 is a PDE that is activated by cGMP and degrades cGMP and cAMP [67].…”