Paroxetine-mediated GRK2 inhibition reverses cardiac dysfunction and remodeling after myocardial infarction.
Paroxetine-mediated GRK2 inhibition reverses cardiac dysfunction and remodeling after myocardial infarction.
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DOI：
10.1126/scitranslmed.aaa0154
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发表时间：
2015-03-04
影响因子：
17.1
通讯作者：
Koch WJ
中科院分区：
文献类型：
--
作者：
Schumacher SM;Gao E;Zhu W;Chen X;Chuprun JK;Feldman AM;Tesmer JJ;Koch WJ
心力衰竭(HF)是一种流行的疾病，与过高的医疗费用有关。G蛋白(异三聚体鸟嘌呤核苷酸结合蛋白)偶联受体2(GRK2)在衰竭的心脏中表达上调，部分原因是GRK2活性增强促进了肾上腺素能信号转导功能障碍和心肌细胞死亡。最近，我们发现选择性5-羟色胺再摄取抑制剂(SSRI)帕罗西汀可以选择性地抑制GRK2。野生型小鼠于心肌梗死后2周开始给予帕罗西汀治疗4周。这些小鼠与氟西汀治疗的小鼠进行比较，氟西汀不抑制GRK2，以控制帕罗西汀的SSRI效应。所有小鼠在治疗前都表现出相似的左心室(LV)功能障碍；然而，尽管对照组和氟西汀组的功能持续下降，但帕罗西汀组的左心室功能和结构显著改善，心衰的几个特征要么被抑制，要么被逆转。基因工程小鼠的使用表明，帕罗西汀通过抑制GRK2发挥作用。帕罗西汀的有益效果明显大于β阻滞剂治疗，后者是目前人类心力衰竭的治疗标准。这些数据表明，帕罗西汀介导的GRK2抑制改善了MI后的心功能，代表了该药物潜在的再利用，也是创新小分子GRK2抑制剂开发的起点。
Heart failure (HF) is a disease of epidemic proportion and is associated with exceedingly high health care costs. G protein (heterotrimeric guanine nucleotide–binding protein)–coupled receptor (GPCR) kinase 2 (GRK2), which is up-regulated in the failing human heart, appears to play a critical role in HF progression in part because enhanced GRK2 activity promotes dysfunctional adrenergic signaling and myocyte death. Recently, we found that the selective serotonin reuptake inhibitor (SSRI) paroxetine could inhibit GRK2 with selectivity over other GRKs. Wild-type mice were treated for 4 weeks with paroxetine starting at 2 weeks after myocardial infarction (MI). These mice were compared with mice treated with fluoxetine, which does not inhibit GRK2, to control for the SSRI effects of paroxetine. All mice exhibited similar left ventricular (LV) dysfunction before treatment; however, although the control and fluoxetine groups had continued degradation of function, the paroxetine group had considerably improved LV function and structure, and several hallmarks of HF were either inhibited or reversed. Use of genetically engineered mice indicated that paroxetine was working through GRK2 inhibition. The beneficial effects of paroxetine were markedly greater than those of β-blocker therapy, a current standard of care in human HF. These data demonstrate that paroxetine-mediated inhibition of GRK2 improves cardiac function after MI and represents a potential repurposing of this drug, as well as a starting point for innovative small-molecule GRK2 inhibitor development.