PICOT increases cardiac contractility by inhibiting PKC味 activity

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• 作者：Jae Gyun Oh^a ; Dongtak Jeong^b ; Hyeseon Cha^a ; Ji Myoung Kim^a ; Ekaterina Lifirsu^a ; Jihwa Kim^a ; Dong Kwon Yang^a ; Chang Sik Park^a ; Changwon Kho^b ; Soonyong Park^a ; Yung Joon Yoo^a ; Do Han Kim^a ; Jaetaek Kim^c ; Roger J. Hajjar^b ; Woo Jin Park^a ; ^{woojinpark@me.com}
• 关键词：PICOT ; PKC味 ; PKC伪 ; PP2A ; Contractility
• 刊名：Journal of Molecular and Cellular Cardiology
• 出版年：2012
• 期刊代码：171_00222828
• 类别：bio
• 出版时间：July, 2012
• 卷：53
• 期：1
• 页码：53-63
• 文件大小：1322 K

摘要

Protein kinase C (PKC)-interacting cousin of thioredoxin (PICOT) has distinct anti-hypertrophic and inotropic functions. We have previously shown that PICOT exerts its anti-hypertrophic effect by inhibiting calcineurin-NFAT signaling through its C-terminal glutaredoxin domain. However, the mechanism underlying the inotropic effect of PICOT is unknown. The results of protein pull-down experiments showed that PICOT directly binds to the catalytic domain of PKC味 through its N-terminal thioredoxin-like domain. Purified PICOT protein inhibited the kinase activity of PKC味 in vitro, which indicated that PICOT is an endogenous inhibitor of PKC味. The inhibition of PKC味 activity with a PKC味-specific pseudosubstrate peptide inhibitor was sufficient to increase the cardiac contractility in vitro and ex vivo. Overexpression of PICOT or inhibition of PKC味 activity down-regulated PKC伪 activity, which led to the elevation of sarcoplasmic reticulum Ca²⁺-ATPase (SERCA) 2a activity, concomitant with the increased phosphorylation of phospholamban (PLB). Overexpression of PICOT or inhibition of PKC味 activity also down-regulated protein phosphatase (PP) 2A activity, which subsequently resulted in the increased phosphorylation of troponin (Tn) I and T, key myofilament proteins associated with the regulation of contractility. PICOT appeared to inhibit PP2A activity through the disruption of the functional PKC味/PP2A complex. In contrast to the overexpression of PICOT or inhibition of PKC味, reduced PICOT expression resulted in up-regulation of PKC伪 and PP2A activities, followed by decreased phosphorylation of PLB, and TnI and T, respectively, supporting the physiological relevance of these events. Transgene- or adeno-associated virus (AAV)-mediated overexpression of PICOT restored the impaired contractility and prevented further morphological and functional deterioration of the failing hearts. Taken together, the results of the present study suggest that PICOT exerts its inotropic effect by negatively regulating PKC伪 and PP2A activities through the inhibition of PKC味 activity. This finding provides a novel insight into the regulation of cardiac contractility.