xu-(许莹)-mcconnell-2026-phosphodiesterase-8-regulation-of-excitation-contraction-coupling-as-a-target-for-cardiovascular.pdf

Heart failure is a major cause of cardiac mortality in the United States and globally. It occurs when the heart cannot pump enough blood to meet the body’s needs, often due to stiffness of the heart muscle or dysfunction in its ability to contract. Cardiac remodeling in heart failure is an adaptive response to this impaired function. Among the pathways involved in this adap- tation, the sympathetic nervous system, specifically, b-adrenergic receptors (b-ARs), plays a central role. Stimulation of b-ARs enhances cardiac contractility by activating protein kinase A (PKA), a key mediator in downstream signaling that regulates excita- tion-contraction coupling (ECC) through ECC-related proteins. A-kinase-anchoring proteins (AKAPs) act as scaffolds for PKA, organizing compartmentalized signaling events. Recent studies have highlighted the role of AKAP12 in recruiting phosphodiester- ase 8 (PDE8) following b-ARs activation. PDE8 is a cyclic adenosine monophosphate (cAMP)-specific phosphodiesterase that hydrolyzes cAMP, thereby limiting the inotropic responses mediated by b-ARs. Although other PDE isoforms (PDE3, PDE4, and PDE5) have been extensively studied and targeted for therapy in heart failure, PDE8 has received relatively little attention. This review discusses the emerging roles of PDE8 across various physiological systems, with a particular focus on the cardiovascular system and its potential as a therapeutic target.