| First Author | Kirchhefer U | Year | 2018 |
| Journal | J Mol Cell Cardiol | Volume | 125 |
| Pages | 195-204 | PubMed ID | 30389400 |
| Mgi Jnum | J:270070 | Mgi Id | MGI:6274582 |
| Doi | 10.1016/j.yjmcc.2018.10.022 | Citation | Kirchhefer U, et al. (2018) Chronic beta-adrenergic stimulation reverses depressed Ca handling in mice overexpressing inhibitor-2 of protein phosphatase 1. J Mol Cell Cardiol 125:195-204 |
| abstractText | RATIONALE: A higher expression/activity of type 1 serine/threonine protein phosphatase 1 (PP1) may contribute to dephosphorylation of cardiac regulatory proteins triggering the development of heart failure. OBJECTIVE: Here, we tested the putatively protective effects of PP1 inhibitor-2 (I2) overexpression using a heart failure model induced by chronic beta-adrenergic stimulation. METHODS AND RESULTS: Transgenic (TG) and wild-type (WT) mice were subjected to isoprenaline (ISO) or isotonic NaCl solution supplied via osmotic minipumps for 7days. I2 overexpression was associated with a depressed PP1 activity. Basal contractility was unchanged in catheterized mice and isolated cardiomyocytes between TG(NaCl) and WT(NaCl). TG(ISO) mice exhibited more fibrosis and a higher expression of hypertrophy marker proteins as compared to WT(ISO). After acute administration of ISO, the contractile response was accompanied by a higher sensitivity in TG(ISO) as compared to WT(ISO). In contrast to basal contractility, the peak amplitude of [Ca]i and SR Ca load were reduced in TG(NaCl) as compared to WT(NaCl). These effects were normalized to WT levels after chronic ISO stimulation. Cardiomyocyte relaxation and [Ca]i decay kinetics were hastened in TG(ISO) as compared to WT(ISO), which can be explained by a higher phospholamban phosphorylation at Ser(16). Chronic catecholamine stimulation was followed by an enhanced expression of GSK3beta, whereas the phosphorylation at Ser(9) was lower in TG as compared to the corresponding WT group. This resulted in a higher I2 phosphorylation that may reactivate PP1. CONCLUSION: Our findings suggest that the basal desensitization of beta-adrenergic signaling and the depressed Ca handling in TG by inhibition of PP1 is restored by a GSK3beta-dependent phosphorylation of I2. |
