Roles and regulation of protein phosphatase 2A (PP2A) in the heart

Abstract

Reversible protein phosphorylation is central to a variety of cardiac processes including excitation-contraction coupling, Ca2+ handling, cell metabolism, myofilament regulation, and cell-cell communication. While kinase pathways linked with elevated adrenergic signaling have been a major focus for the cardiovascular field over the past half century, new findings support the critical role of protein phosphatases in both health and disease. Protein phosphatase 2A (PP2A) is a central cardiac phosphatase that regulates diverse myocyte functions through a host of target molecules. Notably, multiple mechanisms have evolved to dynamically tune PP2A function, including modulation of the composition, phosphorylation, methylation, and localization of PP2A holoenzyme populations. Further, aberrations in this regulation of PP2A function may contribute to cardiac pathophysiology. In summary, PP2A is a critical regulatory molecule in both health and disease, with a myriad of targets in heart. Based on their unique structure, localization, and regulatory properties, PP2A subunits represent exciting therapeutic targets to modulate altered adrenergic signaling in cardiovascular disease.

Tristetraprolin attenuates brain edema in a rat model of cerebral hemorrhage

“…Joe et al () suggested that TTP is effective at inducing inflammatory cytokines such as ILs and TNF‐α. PP2A may induce anti‐apoptotic and anti‐inflammatory activity in TTP, as it negatively regulates apoptosis, inflammation, and cell growth to protect against damage due to stroke, neurodegeneration, and cardiovascular disease (Lubbers & Mohler, ; Seshacharyulu, Pandey, Datta, & Batra, ). Mahtani et al () reported the anti‐inflammatory effects of PP2A in rheumatoid arthritis.…”

Long-Term Oral Administration of Theaphenon-E Improves Cardiomyocyte Mechanics and Calcium Dynamics by Affecting Phospholamban Phosphorylation and ATP Production

“…Many kinases have been implicated in the regulation of Ca 2+ transient, such as PKA, CamKII and PKC [47][48][49]. New findings highlight the role, overlooked for many years, of phosphatases in the fine tuning of the phosphorylation balance of physiologically relevant targets [45,50,51]. Protein phosphatases-1 (PP1) and -2A (PP2A) are responsible for the dephosphorylation of the majority (more than 90%) of phosphoserine/threonine residues in the cardiac cells [52].…”

microRNA signatures of perioperative myocardial injury after elective non-cardiac surgery: prospective observational cohort study

“…36 Reversible protein phosphorylation is essential for excitation-contraction coupling, Ca 2+ handling, cell metabolism, myofilament regulation, and cell-cell communication. 37 ~90% of dephosphorylation events are catalysed by just three phosphatases: PP1, PP2A and PP2B (calcineurin), all of which are regulated by microRNA we identified as changing after surgery. We identified multiple potential PP2A regulatory subunits potentially related to microRNA changes after surgery, which likely reflects the diversity of expression between cardiac cell types, subcellular domains, and disease phenotypes.…”

“…We identified multiple potential PP2A regulatory subunits potentially related to microRNA changes after surgery, which likely reflects the diversity of expression between cardiac cell types, subcellular domains, and disease phenotypes. 37 In the universal presence of a stressor phenotype after surgery, elevations in plasma troponin suggest that loss of cardioprotective mechanisms promote myocardial injury ( Figure 4D). An aberrant inflammatory response, as indicated by the decline in expression levels of the anti-inflammatory microRNA hsa-miR-146a-5p, is a plausible mechanism.…”