Thin filament-based modulation of contractile performance in human heart failure

Article

关键词: PROTEIN-KINASE-C;    FAILING HUMAN HEART;    CARDIAC TROPONIN-I;    DILATED CARDIOMYOPATHY;    MECHANICAL PERFORMANCE;    SARCOPLASMIC-RETICULUM;    MOUSE HEARTS;    PHOSPHORYLATION;    ISOFORMS;    MYOSIN;   

DOI  :  10.1161/01.CIR.0000139334.43109.F9

来源: SCIE

【 摘 要 】

Background - The contribution of the sarcomere's thin filament to the contractile dysfunction of human cardiomyopathy is not well understood. Methods and Results - We have developed techniques to isolate and functionally characterize intact ( native) thin filaments obtained from failing and nonfailing human ventricular tissue. By use of in vitro motility and force assays, native thin filaments from failing ventricular tissue exhibited a 19% increase in maximal velocity but a 27% decrease in maximal contractile force compared with nonfailing myocardium. Native thin filaments isolated from human myocardium after left ventricular assist device support demonstrated a 37% increase in contractile force. Dephosphorylation of failing native thin filaments resulted in a near-normalization of thin-filament function, implying a phosphorylation-mediated mechanism. Tissue expression of the protein kinase C isoforms alpha, beta(1), and beta(2) was increased in failing human myocardium and reduced after left ventricular assist device support. Conclusions - These novel findings demonstrate that ( 1) the thin filament is a key modulator of contractile performance in the failing human heart, ( 2) thin-filament function is restored to near normal levels after LVAD support, and ( 3) the alteration of thin-filament function in failing human myocardium is mediated through phosphorylation, most likely through activation of protein kinase C.

【 授权许可】

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