Day Sharlene M, Westfall Margaret V, Fomicheva Ekaterina V, Hoyer Kirsten, Yasuda Soichiro, La Cross Nathan C, D'Alecy Louis G, Ingwall Joanne S, Metzger Joseph M
Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, Michigan 48109, USA.
Nat Med. 2006 Feb;12(2):181-9. doi: 10.1038/nm1346. Epub 2006 Jan 22.
The myofilament protein troponin I (TnI) has a key isoform-dependent role in the development of contractile failure during acidosis and ischemia. Here we show that cardiac performance in vitro and in vivo is enhanced when a single histidine residue present in the fetal cardiac TnI isoform is substituted into the adult cardiac TnI isoform at codon 164. The most marked effects are observed under the acute challenges of acidosis, hypoxia, ischemia and ischemia-reperfusion, in chronic heart failure in transgenic mice and in myocytes from failing human hearts. In the isolated heart, histidine-modified TnI improves systolic and diastolic function and mitigates reperfusion-associated ventricular arrhythmias. Cardiac performance is markedly enhanced in transgenic hearts during reperfusion despite a high-energy phosphate content similar to that in nontransgenic hearts, providing evidence for greater energetic economy. This pH-sensitive 'histidine button' engineered in TnI produces a titratable molecular switch that 'senses' changes in the intracellular milieu of the cardiac myocyte and responds by preferentially augmenting acute and long-term function under pathophysiological conditions. Myofilament-based inotropy may represent a therapeutic avenue to improve myocardial performance in the ischemic and failing heart.
肌丝蛋白肌钙蛋白I（TnI）在酸中毒和缺血期间收缩功能衰竭的发展中具有关键的同工型依赖性作用。在此我们表明，当胎儿心脏TnI同工型中存在的单个组氨酸残基在密码子164处被替换到成人心脏TnI同工型中时，体外和体内的心脏功能均得到增强。在酸中毒、缺氧、缺血和缺血再灌注的急性挑战下、转基因小鼠的慢性心力衰竭中以及来自衰竭人类心脏的心肌细胞中观察到最显著的效果。在离体心脏中，组氨酸修饰的TnI改善收缩和舒张功能，并减轻再灌注相关的室性心律失常。尽管再灌注期间转基因心脏中的高能磷酸盐含量与非转基因心脏相似，但其心脏功能仍显著增强，这为更高的能量经济性提供了证据。在TnI中设计的这种对pH敏感的“组氨酸按钮”产生了一种可滴定的分子开关，该开关“感知”心肌细胞细胞内环境的变化，并通过在病理生理条件下优先增强急性和长期功能做出反应。基于肌丝的心肌收缩力增强可能代表了一种改善缺血和衰竭心脏心肌功能的治疗途径。
