Overexpression of the cardiac beta(2)-adrenergic receptor and expression of a beta-adrenergic receptor kinase-1 (betaARK1) inhibitor both increase myocardial contractility but have differential effects on susceptibility to ischemic injury.
Overexpression of the cardiac beta(2)-adrenergic receptor and expression of a beta-adrenergic receptor kinase-1 (betaARK1) inhibitor both increase myocardial contractility but have differential effects on susceptibility to ischemic injury.
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心脏β(2)-肾上腺素能受体的过度表达和β-肾上腺素能受体激酶-1 (betaARK1) 抑制剂的表达均可增加心肌收缩力，但对缺血性损伤的易感性有不同的影响。
DOI：
10.1161/01.res.85.11.1077
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发表时间：
1999
影响因子：
20.1
通讯作者：
Murphy,E
中科院分区：
文献类型：
--
作者：
Cross,HR;Steenbergen,C;Lefkowitz,RJ;Koch,WJ;Murphy,E
心脏β2-肾上腺素能受体（β2AR）过表达是治疗心力衰竭的一种潜在的收缩疗法。在正常情况下，过表达β2ARs （TG4s）的小鼠心脏收缩力升高，无不良反应。为了评估β2AR在缺血期间过表达的后果，TG4和野生型小鼠的灌注心脏进行了20分钟的缺血和40分钟的再灌注。缺血时，TG4心肌的ATP和pH值低于野生型。TG4心肌缺血损伤更严重，收缩功能、ATP和磷酸肌酸的缺血后恢复较低。由于β2ARs与β1ARs不同，可以与Gias和Gs结合，因此我们用Gias抑制剂百日咳毒素（PTX）预处理小鼠。PTX治疗增加了TG4心脏的基础收缩力，并消除了对异丙肾上腺素的收缩阻力。缺血时，TG4+PTX组的ATP低于TG4组。TG4+PTX组心脏收缩功能和ATP的恢复低于TG4组。我们还研究了过度表达βARK1 （TGβARK1）或βARK1抑制剂（TGβARKct）的小鼠。TGβARK1心脏的功能、ATP和磷酸肌酸的恢复高于野生型心脏。尽管TGβARKct心脏的基础收缩力升高至与TG4s相同的水平，但缺血损伤并未增加。综上所述，β2AR过表达增加了缺血性损伤，而βARK1过表达具有保护作用。PTX治疗可加重β2AR过表达体的缺血性损伤，提示Gsnot Giactivity加重了损伤。与β2AR过表达不同，βARK1抑制剂的表达增加了基底收缩力，而不增加缺血性损伤，因此暗示了一种更安全的心力衰竭潜在治疗方法。
—Cardiac β2-adrenergic receptor (β2AR) overexpression is a potential contractile therapy for heart failure. Cardiac contractility was elevated in mice overexpressing β2ARs (TG4s) with no adverse effects under normal conditions. To assess the consequences of β2AR overexpression during ischemia, perfused hearts from TG4 and wild-type mice were subjected to 20-minute ischemia and 40-minute reperfusion. During ischemia, ATP and pH fell lower in TG4 hearts than wild type. Ischemic injury was greater in TG4 hearts, as indicated by lower postischemic recoveries of contractile function, ATP, and phosphocreatine. Because β2ARs, unlike β1ARs, couple to Gias well as Gs, we pretreated mice with the Giinhibitor pertussis toxin (PTX). PTX treatment increased basal contractility in TG4 hearts and abolished the contractile resistance to isoproterenol. During ischemia, ATP fell lower in TG4+PTX than in TG4 hearts. Recoveries of contractile function and ATP were lower in TG4+PTX than in TG4 hearts. We also studied mice that overexpressed either βARK1 (TGβARK1) or a βARK1 inhibitor (TGβARKct). Recoveries of function, ATP, and phosphocreatine were higher in TGβARK1 hearts than in wild-type hearts. Despite basal contractility being elevated in TGβARKct hearts to the same level as that of TG4s, ischemic injury was not increased. In summary, β2AR overexpression increased ischemic injury, whereas βARK1 overexpression was protective. Ischemic injury in the β2AR overexpressors was exacerbated by PTX treatment, implying that it was Gsnot Giactivity that enhanced injury. Unlike β2AR overexpression, basal contractility was increased by βARK1 inhibitor expression without increasing ischemic injury, thus implicating a safer potential therapy for heart failure.