PDF(Sci-hub)
Abstract：
Myocardial remodeling in response to chronic myocardial infarction (CMI) progresses through two phases, hypertrophic \"compensation\" and congestive \"decompensation.\" Nothing is known about the ability of uninfarcted myocardium to produce force, velocity, and power during these clinical phases, even though adaptation in these regions likely drives progression of compensation. We hypothesized that enhanced cross-bridge-level contractility underlies mechanical compensation and is controlled in part by changes in the phosphorylation states of myosin regulatory proteins. We induced CMI in rats by left anterior descending coronary artery ligation. We then measured mechanical performance in permeabilized ventricular trabecula taken distant from the infarct zone and assayed myosin regulatory protein phosphorylation in each individual trabecula. During full activation, the compensated myocardium produced twice as much power and 31% greater isometric force compared with noninfarcted controls. Isometric force during submaximal activations was raised >2.4-fold, while power was 2-fold greater. Electron and confocal microscopy demonstrated that these mechanical changes were not a result of increased density of contractile protein and therefore not an effect of tissue hypertrophy. Hence, sarcomere-level contractile adaptations are key determinants of enhanced trabecular mechanics and of the overall cardiac compensatory response. Phosphorylation of myosin regulatory light chain (RLC) increased and remained elevated post-MI, while phosphorylation of myosin binding protein-C (MyBP-C) was initially depressed but then increased as the hearts became decompensated. These sensitivities to CMI are in accordance with phosphorylation-dependent regulatory roles for RLC and MyBP-C in crossbridge function and with compensatory adaptation in force and power that we observed in post-CMI trabeculae.
摘要：
慢性心肌梗死（CMI）的心肌重塑通过两个阶段进行，肥大性“补偿”和充血性“失代偿”。“对未梗死心肌产生力的能力一无所知，速度,在这些临床阶段，即使这些地区的适应可能会推动补偿的进展。我们假设跨桥水平收缩性增强是机械补偿的基础，并且部分受肌球蛋白调节蛋白磷酸化状态变化的控制。我们通过左前降支结扎在大鼠中诱导CMI。然后，我们测量了远离梗塞区的透化心室小梁的机械性能，并测定了每个小梁中肌球蛋白调节蛋白的磷酸化。在完全激活期间，与非梗死对照组相比,代偿心肌产生两倍的功率和31%的等轴力.亚最大激活期间的等距力升高>2.4倍，而功率大了2倍。电子和共聚焦显微镜表明，这些机械变化不是收缩蛋白密度增加的结果，因此不是组织肥大的影响。因此，肌节水平的收缩适应是小梁力学增强和整体心脏代偿反应的关键决定因素。肌球蛋白调节轻链（RLC）的磷酸化增加，并在MI后保持升高，肌球蛋白结合蛋白C（MyBP-C）的磷酸化最初被抑制，但随着心脏失代偿而增加。这些对CMI的敏感性与RLC和MyBP-C在跨桥功能中的磷酸化依赖性调节作用以及我们在CMI后小梁中观察到的力和力的补偿性适应性一致。
