Type 1 Phosphatase, a Negative Regulator of Cardiac Function

Abstract

Increases in type 1 phosphatase (PP1) activity have been observed in end stage human heart failure, but the role of this enzyme in cardiac function is unknown. To elucidate the functional significance of increased PP1 activity, we generated models with (i) overexpression of the catalytic subunit of PP1 in murine hearts and (ii) ablation of the PP1-specific inhibitor. Overexpression of PP1 (threefold) was associated with depressed cardiac function, dilated cardiomyopathy, and premature mortality, consistent with heart failure. Ablation of the inhibitor was associated with moderate increases in PP1 activity (23%) and impaired β-adrenergic contractile responses. Extension of these findings to human heart failure indicated that the increased PP1 activity may be partially due to dephosphorylation or inactivation of its inhibitor. Indeed, expression of a constitutively active inhibitor was associated with rescue of β-adrenergic responsiveness in failing human myocytes. Thus, PP1 is an important regulator of cardiac function, and inhibition of its activity may represent a novel therapeutic target in heart failure.

We gratefully acknowledge L. Cooper and G. Newman for excellent technical assistance, L. J. Field for assistance in generation of the PP1 mice, and J. Robbins for the α-MHC promoter.

This work was supported by National Institutes of Health grants HL64018, HL26057, HL52318, and P40RR12358 (E.G.K.), HL07382 (A.N.C.), MH40899 and DA10044 (P.G. and P.B.A.), and HL06308, Subp.4, and DK36569 (A.A.D.P.-R.).