Interaction of β1-adrenoceptor with RAGE mediates cardiomyopathy via CaMKII signaling.
Interaction of β1-adrenoceptor with RAGE mediates cardiomyopathy via CaMKII signaling.
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β1-肾上腺素受体与 RAGE 的相互作用通过 CaMKII 信号传导介导心肌病。
DOI：
10.1172/jci.insight.84969
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发表时间：
2016
期刊：
影响因子：
8
通讯作者：
Xiao RP
中科院分区：
文献类型：
--
作者：
Zhu W;Tsang S;Browe DM;Woo AY;Huang Y;Xu C;Liu JF;Lv F;Zhang Y;Xiao RP
β1-肾上腺素能受体（β 1 AR）（一种GPCR）和晚期糖基化终产物受体（AGEs）（一种模式识别受体（PRR））的刺激已独立地涉及由各种病因引起的心肌病的发病机制，包括心肌梗死、缺血/再灌注损伤和代谢应激。在这里，我们发现两种截然不同的受体，β 1 AR和β 2 AR，在介导心肌损伤和心肌病后遗症中相互依赖。β 1受体缺乏或抑制可阻断β 1 AR和RAGE介导的心肌细胞死亡和适应不良的重构。阻断或阻断β1AR可完全消除RAGE诱导的有害作用。从机制上讲，β 1 AR和β 2+形成复合物，进而激活Ca 2 +/钙调蛋白依赖性激酶II（CaMKII），导致心肌细胞丢失和心肌重塑。这些结果表明，β 1 AR和β 2 AR不仅在受体水平上发生物理串扰，而且在功能上会聚在共同的介质CaMKII上，突出了β 1 AR和β 2 AR的联合抑制作为治疗多种心血管疾病的更有效的疗法，如心肌梗死、缺血/再灌注损伤和糖尿病心血管并发症。
Stimulation of β1-adrenergic receptor (β1AR), a GPCR, and the receptor for advanced glycation end-products (RAGE), a pattern recognition receptor (PRR), have been independently implicated in the pathogenesis of cardiomyopathy caused by various etiologies, including myocardial infarction, ischemia/reperfusion injury, and metabolic stress. Here, we show that the two distinctly different receptors, β1AR and RAGE, are mutually dependent in mediating myocardial injury and the sequelae of cardiomyopathy. Deficiency or inhibition of RAGE blocks β1AR- and RAGE-mediated myocardial cell death and maladaptive remodeling. Ablation or blockade of β1AR fully abolishes RAGE-induced detrimental effects. Mechanistically, RAGE and β1AR form a complex, which in turn activates Ca2+/calmodulin-dependent kinase II (CaMKII), resulting in loss of cardiomyocytes and myocardial remodeling. These results indicate that RAGE and β1AR not only physically crosstalk at the receptor level, but also functionally converge at the common mediator, CaMKII, highlighting a combined inhibition of RAGE and β1AR as a more effective therapy to treat diverse cardiovascular diseases, such as myocardial infarction, ischemia/reperfusion injury, and diabetic cardiovascular complications.