Ablation of plasma membrane Ca(2+)-ATPase isoform 4 prevents development of hypertrophy in a model of hypertrophic cardiomyopathy.
Ablation of plasma membrane Ca(2+)-ATPase isoform 4 prevents development of hypertrophy in a model of hypertrophic cardiomyopathy.
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DOI：
10.1016/j.yjmcc.2014.09.025
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发表时间：
2014-12
影响因子：
5
通讯作者：
V. Prasad;J. Lorenz;V. Lasko;M. Nieman;Min Jiang;Xu Gao;Jack Rubinstein;D. Wieczorek;G. Shull
中科院分区：
文献类型：
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作者：
V. Prasad;J. Lorenz;V. Lasko;M. Nieman;Min Jiang;Xu Gao;Jack Rubinstein;D. Wieczorek;G. Shull
肌节突变蛋白的表达与肥厚型心肌病（HCM）病理性肥厚的发展之间的联系机制仍知之甚少。我们使用在心脏中表达突变体 (Glu180Gly) α-原肌球蛋白 (Tm180) 的转基因模型研究了质膜 Ca2+-ATP 酶 PMCA4 在 HCM 表型中的作用。免疫印迹分析显示，在 Tm180 疾病发病机制早期，心脏 PMCA4 表达上调。这伴随着 L 型 Ca2+ 通道水平的增加，这与病理性肥大有关。当 Tm180 小鼠与 PMCA4-null 系杂交时，PMCA4 的缺失导致 Tm180/PMCA4-null 双突变小鼠的肥大消失。对 Tm180/PMCA4 缺失心脏的 RT-PCR 分析揭示了胎儿程序的钝化以及促纤维化的 Col1a1 和 Col3a1 基因表达恢复至野生型水平。伴随着 L 型 Ca2+ 通道表达减少和钙调神经磷酸酶活性降低的证据。在 Tm180/PMCA4 缺失的心脏中，代谢底物转运蛋白葡萄糖转运蛋白 4 和肉毒碱棕榈酰转移酶 1b 的表达得以保留，并且各种收缩应激相关蛋白（包括心脏锚蛋白 CARP 和肌联蛋白 N2B 亚型）的 mRNA 水平的 Tm180 相关变化被逆转。在 Tm180/PMCA4 缺失的心脏中，cGMP 水平升高，血管舒张剂刺激的磷蛋白磷酸化升高。这些变化与 Tm180/PMCA4 缺失心脏中左心室舒张末压的急剧降低相关，尽管 Tm180 相关的松弛动力学损伤持续存在，但这种情况还是发生了。这些结果揭示了 PMCA4 在 Tm180 肥大表型中的新颖且特定的作用，PMCA4 缺乏的“保护”作用涵盖了 HCM 相关肥大的多个决定因素。
The mechanisms linking the expression of sarcomeric mutant proteins to the development of pathological hypertrophy in hypertrophic cardiomyopathy (HCM) remain poorly understood. We investigated the role of the plasma membrane Ca2+-ATPase PMCA4 in the HCM phenotype using a transgenic model that expresses mutant (Glu180Gly) α-tropomyosin (Tm180) in heart. Immunoblot analysis revealed that cardiac PMCA4 expression was upregulated early in Tm180 disease pathogenesis. This was accompanied by an increase in levels of the L-type Ca2+-channel, which is implicated in pathological hypertrophy. When Tm180 mice were crossed with a PMCA4-null line, loss of PMCA4 caused the abrogation of hypertrophy in Tm180/PMCA4-null double mutant mice. RT-PCR analysis of Tm180/PMCA4-null hearts revealed blunting of the fetal program and reversion of pro-fibroticCol1a1andCol3a1gene expression to wild-type levels. This was accompanied by evidence of reduced L-type Ca2+-channel expression, and diminished calcineurin activity. Expression of the metabolic substrate transporters glucose transporter 4 and carnitine palmitoyltransferase 1b was preserved and Tm180-related changes in mRNA levels of various contractile stress-related proteins including the cardiac ankyrin protein CARP and the N2B isoform of titin were reversed in Tm180/PMCA4-null hearts. cGMP levels were increased and phosphorylation of vasodilator-stimulated phosphoprotein was elevated in Tm180/PMCA4-null hearts. These changes were associated with a sharp reduction in left ventricular end-diastolic pressure in Tm180/PMCA4-null hearts, which occurred despite persistence of Tm180-related impairment of relaxation dynamics. These results reveal a novel and specific role for PMCA4 in the Tm180 hypertrophic phenotype, with the “protective” effects of PMCA4 deficiency encompassing multiple determinants of HCM-related hypertrophy.