MLP 和 CARP 与扩张型心肌病中的慢性 PKCα 信号传导有关。
MLP and CARP are linked to chronic PKCα signalling in dilated cardiomyopathy.
机构信息
School of Medicine, University of California, San Diego, La Jolla CA-92093, USA.
BHF Centre of Research Excellence Oxford, Division of Cardiovascular Medicine, Radcliffe Department of Medicine, University of Oxford, Oxford OX3 9DU, UK.
出版信息
Nat Commun. 2016 Jun 29;7:12120. doi: 10.1038/ncomms12120.
MLP (muscle LIM protein)-deficient mice count among the first mouse models for dilated cardiomyopathy (DCM), yet the exact role of MLP in cardiac signalling processes is still enigmatic. Elevated PKCα signalling activity is known to be an important contributor to heart failure. Here we show that MLP directly inhibits the activity of PKCα. In end-stage DCM, PKCα is concentrated at the intercalated disc of cardiomyocytes, where it is sequestered by the adaptor protein CARP in a multiprotein complex together with PLCβ1. In mice deficient for both MLP and CARP the chronic PKCα signalling chain at the intercalated disc is broken and they remain healthy. Our results suggest that the main role of MLP in heart lies in the direct inhibition of PKCα and that chronic uninhibited PKCα activity at the intercalated disc in the absence of functional MLP leads to heart failure.
MLP（肌肉 LIM 蛋白）缺陷型小鼠是扩张型心肌病（DCM）的首批小鼠模型之一，但 MLP 在心脏信号转导过程中的确切作用仍不清楚。已知 PKCα 信号活性升高是心力衰竭的一个重要贡献因素。在这里，我们表明 MLP 可直接抑制 PKCα 的活性。在终末期 DCM 中，PKCα 集中在心肌细胞的闰盘处，在那里它与 PLCβ1 一起被衔接蛋白 CARP 隔离在一个多蛋白复合物中。在同时缺乏 MLP 和 CARP 的小鼠中，闰盘处的慢性 PKCα 信号链被打断，它们仍然保持健康。我们的结果表明，MLP 在心脏中的主要作用在于直接抑制 PKCα，并且在缺乏功能性 MLP 的情况下，闰盘处的慢性未被抑制的 PKCα 活性会导致心力衰竭。
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