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(Circulation Research. 2007;101:195.)
© 2007 American Heart Association, Inc.

Integrative Physiology

Augmented Protein Kinase C-–Induced Myofilament Protein Phosphorylation Contributes to Myofilament Dysfunction in Experimental Congestive Heart Failure

Rashad J. Belin, Marius P. Sumandea, Edward J. Allen, Kelly Schoenfelt, Helen Wang, R. John Solaro, Pieter P. de Tombe

From the Department of Physiology and Biophysics, Center for Cardiovascular Research, University of Illinois at Chicago.

Correspondence to Dr Pieter P. de Tombe, PhD, University of Illinois at Chicago, Department of Physiology and Biophysics, 835 S Wolcott (M/C 901), Chicago, IL 60612. E-mail pdetombe{at}uic.edu

It is becoming clear that upregulated protein kinase C (PKC) signaling plays a role in reduced ventricular myofilament contractility observed in congestive heart failure. However, data are scant regarding which PKC isozymes are involved. There is evidence that PKC- may be of particular importance. Here, we examined PKC- quantity, activity, and signaling to myofilaments in chronically remodeled myocytes obtained from rats in either early heart failure or end-stage congestive heart failure. Immunoblotting revealed that PKC- expression and activation was unaltered in early heart failure but increased in end-stage congestive heart failure. Left ventricular myocytes were isolated by mechanical homogenization, Triton-skinned, and attached to micropipettes that projected from a force transducer and motor. Myofilament function was characterized by an active force–[Ca²⁺] relation to obtain Ca²⁺-saturated maximal force (F_max) and myofilament Ca²⁺ sensitivity (indexed by EC₅₀) before and after incubation with PKC-, protein phosphatase type 1 (PP1), or PP2a. PKC- treatment induced a 30% decline in F_max and 55% increase in the EC₅₀ in control cells but had no impact on myofilament function in failing cells. PP1-mediated dephosphorylation increased F_max (15%) and decreased EC₅₀ (20%) in failing myofilaments but had no effect in control cells. PP2a-dependent dephosphorylation had no effect on myofilament function in either group. Lastly, PP1 dephosphorylation restored myofilament function in control cells hyperphosphorylated with PKC-. Collectively, our results suggest that in end-stage congestive heart failure, the myofilament proteins exist in a hyperphosphorylated state attributable, in part, to increased activity and signaling of PKC-.

Key Words: heart failure • protein kinase C- • myofilament proteins • protein phosphatase type 1 • phosphorylation

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