LeWinter Martin M, Granzier Henk L
*Cardiology Unit, Fletcher Allen Health Care, Department of Medicine, University of Vermont, Burlington, VT; and †Sarver Molecular Cardiovascular Research Program, and ‡Department of Physiology, University of Arizona, Tucson, AZ.
J Cardiovasc Pharmacol. 2014 Mar;63(3):207-12. doi: 10.1097/FJC.0000000000000007.
The giant sarcomeric protein titin is a key determinant of myocardial passive stiffness and stress-sensitive signaling. Titin stiffness is modulated by isoform variation, phosphorylation by protein kinases, and, possibly, oxidative stress through disulfide bond formation. Titin has also emerged as an important human disease gene. Early studies in patients with dilated cardiomyopathy (DCM) revealed shifts toward more compliant isoforms, an adaptation that offsets increases in passive stiffness based on the extracellular matrix. Similar shifts are observed in heart failure with preserved ejection fraction. In contrast, hypophosphorylation of PKA/G sites contributes to a net increase in cardiomyocyte resting tension in heart failure with preserved ejection fraction. More recently, titin mutations have been recognized as the most common etiology of inherited DCM. In addition, some DCM-causing mutations affect RBM20, a titin splice factor. Titin mutations are a rare cause of hypertrophic cardiomyopathy and also underlie some cases of arrhythmogenic right ventricular dysplasia. Finally, mutations of genes encoding proteins that interact with and/or bind to titin are responsible for both DCM and hypertrophic cardiomyopathy. Targeting titin as a therapeutic strategy is in its infancy, but it could potentially involve manipulation of isoforms, posttranslational modifications, and upregulation of normal protein in patients with disease-causing mutations.
巨大的肌节蛋白肌联蛋白是心肌被动僵硬度和应力敏感信号传导的关键决定因素。肌联蛋白的僵硬度受同工型变异、蛋白激酶磷酸化以及可能通过二硫键形成的氧化应激调节。肌联蛋白也已成为一种重要的人类疾病基因。早期对扩张型心肌病（DCM）患者的研究发现，其同工型向更具顺应性的方向转变，这种适应性变化抵消了基于细胞外基质的被动僵硬度增加。在射血分数保留的心力衰竭患者中也观察到类似的转变。相反，在射血分数保留的心力衰竭患者中，蛋白激酶A/G位点的低磷酸化导致心肌细胞静息张力净增加。最近，肌联蛋白突变已被确认为遗传性DCM最常见的病因。此外，一些导致DCM的突变会影响肌联蛋白剪接因子RBM20。肌联蛋白突变是肥厚型心肌病的罕见病因，也是一些致心律失常性右室发育不良病例的基础。最后，编码与肌联蛋白相互作用和/或结合的蛋白质的基因突变是DCM和肥厚型心肌病的病因。将肌联蛋白作为一种治疗策略仍处于起步阶段，但它可能涉及对同工型的操纵、翻译后修饰以及对致病突变患者中正常蛋白质的上调。
