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Science :收缩性心力衰竭治疗新方略

来源:EurekAlert! 2011-03-18 13:18

这种叫做omecamtiv mercabil的分子过去被发现可激活心脏的肌球蛋白,即心肌中主要的产生动力的蛋白。 如今,研究人员说,它是通过加快肌球蛋白向产力状态的转换来实现这一作用的,这一过程可增加能够结合肌动蛋白的肌球蛋白数目,并提高心肌的收缩能力。 Fady Malik及其同事描述了这种分子究竟是如何作用于心脏的,他们在犬类和啮齿类动物中证明了其功效。这些结果提示,该药最终也能为治疗人类的收缩性心力衰竭提供新的方略。 研究人员发现,omecamtiv mercabil这种小分子会与肌球蛋白的非活性部位结合以增加ATP的利用率,加快对肌动蛋白依赖的磷酸释放并减缓ADP的释放。 通过易化这些过程,该药快速地将肌球蛋白引导至心肌收缩所必须的可强力结合肌动蛋白的状态。 研究人员观察到,该分子不但能够增加健康动物的心脏功能,它还能够增加那些有心衰迹象动物的心脏功能。 Malik及其同事提出,将来,这种药物也许可以消除在其它的非直接作用于肌动蛋白的心脏病药物中所见到的那些有害的副作用。 在一篇观点栏目中,Leslie Leinwand 和 Richard Moss更为详细地对这些发现进行了解释。(生物谷Bioon.com)

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Science DOI: 10.1126/science.1200113

Cardiac Myosin Activation: A Potential Therapeutic Approach for Systolic Heart Failure

Fady I. Malik1,*, James J. Hartman1, Kathleen A. Elias1, Bradley P. Morgan1, Hector Rodriguez1, Katju?a Brejc1, Robert L. Anderson1, Sandra H. Sueoka1, Kenneth H. Lee1, Jeffrey T. Finer1, Roman Sakowicz1, Ramesh Baliga1, David R. Cox1, Marc Garard1, Guillermo Godinez1, Raja Kawas1, Erica Kraynack1, David Lenzi1, Pu Ping Lu1, Alexander Muci1, Congrong Niu1, Xiangping Qian1, Daniel W. Pierce1, Maria Pokrovskii1, Ion Suehiro1, Sheila Sylvester1, Todd Tochimoto1, Corey Valdez1, Wenyue Wang1, Tatsuo Katori2, David A. Kass2, You-Tang Shen3,5, Stephen F. Vatner3,4, and David J. Morgans1

Decreased cardiac contractility is a central feature of systolic heart failure. Existing drugs increase cardiac contractility indirectly through signaling cascades but are limited by their mechanism-related adverse effects. To avoid these limitations, we previously developed omecamtiv mecarbil, a small-molecule, direct activator of cardiac myosin. Here, we show that it binds to the myosin catalytic domain and operates by an allosteric mechanism to increase the transition rate of myosin into the strongly actin-bound force-generating state. Paradoxically, it inhibits adenosine 5′-triphosphate turnover in the absence of actin, which suggests that it stabilizes an actin-bound conformation of myosin. In animal models, omecamtiv mecarbil increases cardiac function by increasing the duration of ejection without changing the rates of contraction. Cardiac myosin activation may provide a new therapeutic approach for systolic heart failure.

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