Chronic β-adrenergic stimulation reverses depressed Ca handling in mice overexpressing inhibitor-2 of protein phosphatase 1

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 (I 2 ) 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. I 2 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 I 2 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 I 2 .