Chronic β-adrenergic stimulation reverses depressed Ca handling in mice overexpressing inhibitor-2 of protein phosphatase 1. (December 2018)

• Record Type: Journal Article
• Authors: Kirchhefer, Uwe; Hammer, Elke; Heinick, Alexander; Herpertz, Thomas; Isensee, Gunnar; Müller, Frank U.; Neumann, Joachim; Schulte, Kirsten; Seidl, Matthias D.; Boknik, Peter; Schulte, Jan S.
• Is Part Of: Journal of molecular and cellular cardiology. Volume 125(2018)
• Page Start: 195
• Page End: 204
• Publication Date: 2018-12
• Subjects: Protein phosphatase 1 -- Inhibitor-2 -- Heart failure -- β-adrenergic stimulation -- Ca handling; Cardiology -- Periodicals; Heart Diseases -- Periodicals; Molecular Biology -- Periodicals; Cardiologie -- Périodiques; Cardiology; Electronic journals; Periodicals; 616.12
• DOI: 10.1016/j.yjmcc.2018.10.022
• Languages: English
• ISSNs: 0022-2828

Abstract

Abstract: 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 β-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 7 days. 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 GSK3β, 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 β-adrenergic signaling and the depressed Ca handling in TG by inhibition of PP1 is restored by a GSK3β-dependent phosphorylation of I2 .