| First Author | Kang MY | Year | 2010 |
| Journal | Circ Res | Volume | 107 |
| Issue | 7 | Pages | 903-12 |
| PubMed ID | 20689063 | Mgi Jnum | J:178202 |
| Mgi Id | MGI:5297672 | Doi | 10.1161/CIRCRESAHA.110.220772 |
| Citation | Kang MY, et al. (2010) Receptor-independent cardiac protein kinase Calpha activation by calpain-mediated truncation of regulatory domains. Circ Res 107(7):903-12 |
| abstractText | RATIONALE: Protein kinase (PK)Cs and calpain cysteine proteases are highly expressed in myocardium. Ischemia produces calcium overload that activates calpains and conventional PKCs. However, calpains can proteolytically process PKCs, and the potential in vivo consequences of this interaction are unknown. OBJECTIVE: To determine the biochemical and pathophysiological consequences of calpain-mediated cardiac PKCalpha proteolysis. METHODS AND RESULTS: Isolated mouse hearts subjected to global ischemia/reperfusion demonstrated cleavage of PKCalpha. Calpain 1 overexpression was not sufficient to produce PKCalpha cleavage in normal hearts, but ischemia-induced myocardial PKCalpha cleavage and myocardial injury were greatly increased by cardiac-specific expression of calpain 1. In contrast, calpain 1 gene ablation or inhibition with calpastatin prevented ischemia/reperfusion induced PKCalpha cleavage; infarct size was decreased and ventricular function enhanced in infarcted calpain 1 knockout hearts. To determine consequences of PKCalpha fragmentation on myocardial protein phosphorylation, transgenic mice were created conditionally expressing full-length PKCalpha or its N-terminal and C-terminal calpain 1 cleavage fragments. Two-dimensional mapping of ventricular protein extracts showed a distinct PKCalpha phosphorylation profile that was exaggerated and distorted in hearts expressing the PKCalpha C-terminal fragment. MALDI mass spectroscopy revealed hyperphosphorylation of myosin-binding protein C and phosphorylation of atypical substrates by the PKCalpha C-terminal fragment. Expression of parent PKCalpha produced a mild cardiomyopathy, whereas myocardial expression of the C-terminal PKCalpha fragment induced a disproportionately severe, rapidly lethal cardiomyopathy. CONCLUSIONS: Proteolytic processing of PKCalpha by calcium-activated calpain activates pathological cardiac signaling through generation of an unregulated and/or mistargeted kinase. Production of the PKCalpha C-terminal fragment in ischemic hearts occurs via a receptor-independent mechanism. |
