Cardiovascular Division, Department of Medicine, University of Virginia Medical Center, Charlottesville, Virginia, USA.
Clin Transl Sci. 2012 Jun;5(3):235-42. doi: 10.1111/j.1752-8062.2012.00403.x. Epub 2012 Mar 27.
Phospholemman (PLM) regulates Na(+) , Ca(2+) and contractility through its interactions with Na(+)-K(+)-ATPase (NKA) and Na(+) /Ca(2+) exchanger (NCX1) in the heart. Both expression and phosphorylation of PLM are altered after myocardial infarction (MI) and heart failure. We tested the hypothesis that absence of PLM regulation of NKA and NCX1 in PLM-knockout (KO) mice is detrimental. Three weeks after MI, wild-type (WT) and PLM-KO hearts were similarly hypertrophied. PLM expression was lower but fractional phosphorylation was higher in WT-MI compared to WT-sham hearts. Left ventricular ejection fraction was severely depressed in WT-MI but significantly less depressed in PLM-KO-MI hearts despite similar infarct sizes. Compared with WT-sham myocytes, the abnormal [Ca(2+) ], transient and contraction amplitudes observed in WT-MI myocytes were ameliorated by genetic absence of PLM. In addition, NCX1 current was depressed in WT-MI but not in PLM-KO-MI myocytes. Despite improved myocardial and myocyte performance, PLM-KO mice demonstrated reduced survival after MI. Our findings indicate that alterations in PLM expression and phosphorylation are important adaptations post-MI, and that complete absence of PLM regulation of NKA and NCX1 is detrimental in post-MI animals.
磷调节蛋白 (PLM) 通过与心脏中的 Na(+)-K(+)-ATP 酶 (NKA) 和 Na(+)/Ca(2+) 交换器 (NCX1) 的相互作用来调节 Na(+) 、Ca(2+) 和收缩性。心肌梗死后 (MI) 和心力衰竭后，PLM 的表达和磷酸化都会发生改变。我们假设 PLM 敲除 (KO) 小鼠中 PLM 对 NKA 和 NCX1 的调节缺失是有害的。MI 后 3 周，野生型 (WT) 和 PLM-KO 心脏均发生相似的肥大。与 WT 假手术相比，WT-MI 中的 PLM 表达降低，但分数磷酸化增加。尽管梗死面积相似，但 WT-MI 中的左心室射血分数严重降低，但在 PLM-KO-MI 心脏中明显降低。与 WT 假手术心肌细胞相比，WT-MI 心肌细胞中观察到的异常 [Ca(2+) ]、瞬时和收缩幅度在 PLM 缺失的情况下得到改善。此外，NCX1 电流在 WT-MI 中被抑制，但在 PLM-KO-MI 心肌细胞中未被抑制。尽管心肌和心肌细胞的功能得到改善，但 PLM-KO 小鼠在 MI 后生存率降低。我们的发现表明，PLM 表达和磷酸化的改变是 MI 后重要的适应，而 PLM 对 NKA 和 NCX1 的完全调节缺失在 MI 后动物中是有害的。
