Hanft Laurin M, Emter Craig A, McDonald Kerry S
Department of Medical Pharmacology and Physiology, School of Medicine, University of Missouri, Columbia, Missouri; and.
Department of Biomedical Sciences, College of Veterinary Medicine, University of Missouri, Columbia, Missouri.
Am J Physiol Heart Circ Physiol. 2017 Jul 1;313(1):H103-H113. doi: 10.1152/ajpheart.00069.2017. Epub 2017 Apr 28.
Heart failure arises, in part, from a constellation of changes in cardiac myocytes including remodeling, energetics, Ca handling, and myofibrillar function. However, little is known about the changes in myofibrillar contractile properties during the progression from hypertension to decompensated heart failure. The aim of the present study was to provide a comprehensive assessment of myofibrillar functional properties from health to heart disease. A rodent model of uncontrolled hypertension was used to test the hypothesis that myocytes in compensated hearts exhibit increased force, higher rates of force development, faster loaded shortening, and greater power output; however, with progression to overt heart failure, we predicted marked depression in these contractile properties. We assessed contractile properties in skinned cardiac myocyte preparations from left ventricles of Wistar-Kyoto control rats and spontaneous hypertensive heart failure (SHHF) rats at ~3, ~12, and >20 mo of age to evaluate the time course of myofilament properties associated with normal aging processes compared with myofilaments from rats with a predisposition to heart failure. In control rats, the myofilament contractile properties were virtually unchanged throughout the aging process. Conversely, in SHHF rats, the rate of force development, loaded shortening velocity, and power all increased at ~12 mo and then significantly fell at the >20-mo time point, which coincided with a decrease in left ventricular fractional shortening. Furthermore, these changes occurred independent of changes in β-myosin heavy chain but were associated with depressed phosphorylation of myofibrillar proteins, and the fall in loaded shortening and peak power output corresponded with the onset of clinical signs of heart failure. This novel study systematically examined the power-generating capacity of cardiac myofilaments during the progression from hypertension to heart disease. Previously undiscovered changes in myofibrillar power output were found and were associated with alterations in myofilament proteins, providing potential new targets to exploit for improved ventricular pump function in heart failure.
心力衰竭部分源于心肌细胞的一系列变化，包括重塑、能量代谢、钙处理和肌原纤维功能。然而，从高血压发展到失代偿性心力衰竭过程中肌原纤维收缩特性的变化却知之甚少。本研究的目的是全面评估从健康到心脏病状态下肌原纤维的功能特性。使用未控制高血压的啮齿动物模型来检验以下假设：代偿性心脏中的心肌细胞表现出更大的力量、更高的力量发展速率、更快的负荷缩短速度和更大的功率输出；然而，随着病情发展至明显的心力衰竭，我们预测这些收缩特性会显著降低。我们评估了来自Wistar-Kyoto对照大鼠和自发性高血压心力衰竭（SHHF）大鼠左心室的皮肤心肌细胞制剂在约3个月、约12个月和大于20个月龄时的收缩特性，以评估与正常衰老过程相关的肌丝特性的时间进程，并与易患心力衰竭大鼠的肌丝进行比较。在对照大鼠中，整个衰老过程中肌丝收缩特性几乎没有变化。相反，在SHHF大鼠中，力量发展速率、负荷缩短速度和功率在约12个月时均增加，然后在大于20个月的时间点显著下降，这与左心室缩短分数的降低相一致。此外，这些变化与β-肌球蛋白重链的变化无关，但与肌原纤维蛋白磷酸化降低有关，负荷缩短和峰值功率输出的下降与心力衰竭临床症状的出现相对应。这项新研究系统地研究了从高血压到心脏病发展过程中心肌肌丝的发电能力。发现了以前未发现的肌原纤维功率输出变化，这些变化与肌丝蛋白的改变有关，为改善心力衰竭时心室泵功能提供了潜在的新靶点。
