Paroxetine Attenuates Cardiac Hypertrophy Via Blocking GRK2 and ADRB1 Interaction in Hypertension.
Paroxetine Attenuates Cardiac Hypertrophy Via Blocking GRK2 and ADRB1 Interaction in Hypertension.
复制标题
帕罗西汀通过阻断高血压中 GRK2 和 ADRB1 的相互作用来减轻心脏肥大
DOI：
10.1161/jaha.120.016364
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发表时间：
2021-01-05
影响因子：
5.4
通讯作者：
Cai J
中科院分区：
文献类型：
--
作者：
Sun X;Zhou M;Wen G;Huang Y;Wu J;Peng L;Jiang W;Yuan H;Lu Y;Cai J
肾上腺素能受体β 1（adrenergic receptor beta 1，ADRB 1）对神经内分泌刺激有反应，对高血压有重要意义。GRK 2（G蛋白偶联受体激酶2）是许多G蛋白偶联受体和后续细胞信号级联的重要调节因子，但其作为ADRB 1和高血压相关心脏肥大的调节因子的作用仍有待阐明。在本研究中，我们发现GRK 2和ADRB 1在外周血单个核细胞中的表达与高血压患者的血压水平呈正相关，并与心脏中的表达呈正相关。体外证据显示ADRB 1和GRK 2的直接相互作用以及GRK 2的遗传缺失阻断了肾上腺素诱导的心肌细胞肥大和纤维化基因的上调。同时，我们发现一种选择性5-羟色胺再摄取抑制剂帕罗西汀可以特异性阻断GRK 2和ADRB 1的相互作用。在体内，帕罗西汀治疗可改善动物模型中高血压诱导的心脏肥大、功能障碍和纤维化。我们发现，帕罗西汀抑制交感神经兴奋和增加肾上腺素能受体的敏感性，儿茶酚胺。帕罗西汀治疗还阻断肾上腺素诱导的肥大和纤维化基因的上调以及心肌细胞中的ADRB 1内化。帕罗西汀联合给药进一步增强了美托洛尔诱导的血压和心率降低，进一步减轻了自发性高血压大鼠的心脏肥大。此外，在伴有抑郁症的高血压患者中，我们观察到与其他类型的抗抑郁药相比，帕罗西汀治疗的患者心脏重塑不太严重。帕罗西汀通过阻断GRK 2介导的ADRB 1激活和内化，在高血压背景下促进ADRB 1敏感性并部分减轻心脏肥大。
ADRB1 (adrenergic receptor beta 1) responds to neuroendocrine stimulations, which have great implications in hypertension. GRK2 (G protein‐coupled receptor kinase 2) is an essential regulator for many G protein‐coupled receptors and subsequent cell signaling cascades, but its role as a regulator of ADRB1 and associated cardiac hypertrophy in hypertension remains to be elucidated. In this study, we found the expressions of GRK2 and ADRB1 in peripheral blood mononuclear cells were positively associated with blood pressure levels in hypertensive patients and with their expression in heart. In vitro evidence showed a direct interaction in ADRB1 and GRK2 and genetic depletion of GRK2 blocks epinephrine‐induced upregulation of hypertrophic and fibrotic genes in cardiomyocytes. Meanwhile, we discovered a selective serotonin reuptake inhibitor paroxetine specifically blockades GRK2 and ADRB1 interaction. In vivo, paroxetine treatment ameliorates hypertension‐induced cardiac hypertrophy, dysfunction, and fibrosis in animal models. We found that paroxetine suppressed sympathetic overdrive and increased the adrenergic receptor sensitivity to catecholamines. Paroxetine treatment also blocks epinephrine‐induced upregulation of hypertrophic and fibrotic genes as well as ADRB1 internalization in cardiomyocytes. Coadministration of paroxetine further potentiates metoprolol‐induced reductions in blood pressure and heart rate, further attenuating cardiac hypertrophy in spontaneously hypertensive rats. Furthermore, in patients with hypertension accompanied with depression, we observed that cardiac remodeling was less severe in those with paroxetine treatment compared with those with other types of anti‐depressive agents. Paroxetine promotes ADRB1 sensitivity and attenuates cardiac hypertrophy partially via blocking GRK2‐mediated ADRB1 activation and internalization in the context of hypertension.