Clin Res Cardiol (2023). https://doi.org/10.1007/s00392-023-02180-w

Combined cardiac overexpression of protein phosphatases (PP) PP5 and PP2C leads to systolic heart failure

R. Schwarz1, U. Gergs1, K. Hadová2, J. Klimas2, J. Neumann1

1Institut für Pharmakologie und Toxikologie, Medizinische Fakultät der Martin-Luther-Universität Halle-Wittenberg, Halle (Saale); 2Faculty of Pharmacy, Department of Pharmacology and Toxicology, Bratislava, SK;

We have previously reported that cardiac overexpression of PP2C only or PP5 only leads to modest cardiac hypertrophy after six months of age in transgenic mice. Overexpression was generated utilizing a cardiac α-myosin heavy chain promotor. We hypothesized that dual overexpression of PP5 and PP2C leads to heart failure. Therefore, we crossbred mice overexpressing PP5 and PP2C and thus we obtained four genotypes namely wild type mice (WT), PP2C-TG, PP5-TG and DT (=PP2C X PP5). We followed the animals likewise for six months. There was an increase of the relative heart weight by 24 % in DT compared to WT (10.1 ± 0.40 vs. 8.14 ± 0.45, p < 0.05, n = 8-11). This was accompanied by histologically measureable fibrosis in DT and impaired systolic function with an ejection fraction of only 47.1 % ± 5.01 % in DT compared to 65.4 % ± 4.49 % in WT (n = 3-7). Likewise, the increase in ejection fraction after intraperitoneal injection of isoprenaline (1 mM / 100 µl) was less in DT compared to WT values (71.0 % ± 8.85 % vs. 94.6 % ± 6.42 %, p < 0.05, n = 3-6). Similarly to the heart weight we noticed a gradial increase in the expression of the mRNA for the atrial natriuretic peptide from values in wild type hearts (1.00 ± 0.33, n = 6), in PP5-TG (2.40 ± 0.42, n = 6), in PP2C-TG (2.47 ± 1.65, n = 6) and DT (5.14 ± 0.75, p < 0.05, n = 10). In Langendorff preparations from DT, force of contraction after ischemia and reperfusion was decreased by 28 % compared to WT (86.7 % ± 6.36 % vs. 111 % ± 9.74 %, p < 0.05, n = 5-9). The effect of isoprenaline to increase the phosphorylation state of phospholamban in these perfused hearts was smaller in PP5-TG and PP2C-TG than in WT and had an intermediate value for DT. We conclude that combined overexpression of PP5 and PP2C can alter the phosphorylation state of cardiac regulatory proteins which might explain the observed cardiac hypertrophy and systolic heart failure in DT. We speculate that similar mechanism might be operative in some patients with heart failure and drugs that target PP5 and PP2C might be useful for some heart failure patients.

https://dgk.org/kongress_programme/jt2023/aP1779.html