Key result
Cardiac co-overexpression of PP2A and PP5 in mice was detrimental to animal survival and cardiac function, potentially driven by dephosphorylation of regulatory proteins, fibrosis, and inflammation.
Why the study?
The study was conducted to investigate the potential pathophysiological role of the serine/threonine phosphatases PP2Acalpha and PP5 in the mammalian heart.
Co-overexpression of PP2A and PP5 in the murine heart leads to severe cardiac dysfunction, fibrosis, and increased mortality, highlighting the pathophysiological role of these phosphatases.
Suggests PP2A/PP5 as potential HF targets; leaves open human translation and therapeutic testing.
As part of our ongoing studies on the potential pathophysiological role of serine/threonine phosphatases (PP) in the mammalian heart, we have generated transgenic mice with cardiac muscle cell-specific overexpression of PP2Acα (PP2A) and PP5 (PP5). For further studies we crossbred PP2A and PP5 mice to obtain PP2AxPP5 double transgenic mice (PP2AxPP5, DT) and compared them with littermate wild-type mice (WT) serving as a control. The mortality of DT mice was greatly enhanced vs. other genotypes. Cardiac fibrosis was noted histologically and mRNA levels of collagen 1α, collagen 3α and fibronectin 1 were augmented in DT. DT and PP2A mice exhibited an increase in relative heart weight. The ejection fraction (EF) was reduced in PP2A and DT but while the EF of PP2A was nearly normalized after β-adrenergic stimulation by isoproterenol, it was almost unchanged in DT. Moreover, left atrial preparations from DT were less sensitive to isoproterenol treatment both under normoxic conditions and after hypoxia. In addition, levels of the hypertrophy markers atrial natriuretic peptide and B-type natriuretic peptide as well as the inflammation markers interleukin 6 and nuclear factor kappa B were increased in DT. PP2A enzyme activity was enhanced in PP2A vs. WT but similar to DT. This was accompanied by a reduced phosphorylation state of phospholamban at serine-16. Fittingly, the relaxation times in left atria from DT were prolonged. In summary, cardiac co-overexpression of PP2A and PP5 were detrimental to animal survival and cardiac function, and the mechanism may involve dephosphorylation of important regulatory proteins but also fibrosis and inflammation.
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Dörner et al. (2021) studied Systolic Cardiac Dysfunction. Cardiac co-overexpression of PP2A and PP5 (PP2AxPP5 double transgenic mice) vs. Littermate wild-type mice (WT) was evaluated on Mortality and cardiac function (ejection fraction). Cardiac co-overexpression of PP2A and PP5 in mice was detrimental to animal survival and cardiac function, potentially driven by dephosphorylation of regulatory proteins, fibrosis, and inflammation.
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