Negative impact of β-arrestin-1 on post-myocardial infarction heart failure via cardiac and adrenal-dependent neurohormonal mechanisms.
Negative impact of β-arrestin-1 on post-myocardial infarction heart failure via cardiac and adrenal-dependent neurohormonal mechanisms.
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β-arrestin-1 通过心脏和肾上腺依赖性神经激素机制对心肌梗死后心力衰竭产生负面影响。
DOI：
10.1161/hypertensionaha.113.02043
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发表时间：
2014-02
期刊：
影响因子：
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通讯作者：
Lymperopoulos A
中科院分区：
文献类型：
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作者：
Bathgate-Siryk A;Dabul S;Pandya K;Walklett K;Rengo G;Cannavo A;De Lucia C;Liccardo D;Gao E;Leosco D;Koch WJ;Lymperopoulos A
β抑制蛋白(βarr)-1和-2 （βarrs）是通用的G蛋白偶联受体适配器蛋白，通过βAR脱敏和下调负调控心脏β -肾上腺素能受体（βAR）的功能。此外，它们介导不依赖于G蛋白的βAR信号传导，这可能对心脏有益，例如抗凋亡。然而，每种βarr亚型在慢性心力衰竭（HF）的分子标志——心脏βAR功能障碍中的具体作用尚不清楚。此外，肾上腺βarr1通过慢性增加肾上腺生成，从而增加循环中的醛固酮和儿茶酚胺水平，从而加重心衰。在这里，我们试图通过检测βarr1基因缺失对正常和心肌梗死后心功能和形态的影响来描述βarr1在心肌梗死后（MI） HF中的具体作用。我们研究了βarr1敲除（βarr1KO）小鼠和野生型（WT）对照小鼠在正常情况下和心肌梗死手术后的情况。与WT相比，正常（假手术）βarr1KO表现出增强的βar依赖性收缩力，心肌梗死后βarr1KO表现出增强的整体心功能（和βar依赖性收缩力）。与心肌梗死后WT相比，心肌梗死后βarr1KO也显示出生存率增加，心肌梗死面积、细胞凋亡、不良重构以及循环儿茶酚胺和醛固酮减少。其潜在的机制一方面是由于心脏βarr1缺失导致心脏βAR脱敏，从而提高了βAR密度和促收缩信号，从而改善了心脏βAR信号传导和功能；另一方面由于肾上腺βarr1缺失导致心脏βAR脱敏，从而导致儿茶酚胺和醛固酮循环水平降低。因此，βarr1通过心脏和肾上腺的作用，对心脏结构和功能有害，并显著加剧心肌梗死后HF。
βarrestin (βarr)-1 and -2 (βarrs) are universal G protein-coupled receptor adapter proteins that negatively regulate cardiac β–adrenergic receptor (βAR) function via βAR desensitization & downregulation. In addition, they mediate G protein-independent βAR signaling, which might be beneficial, e.g. antiapoptotic, for the heart. However, the specific role(s) of each βarr isoform in cardiac βAR dysfunction, the molecular hallmark of chronic heart failure (HF), remain unknown. Furthermore, adrenal βarr1 exacerbates HF by chronically enhancing adrenal production, and hence circulating levels of aldosterone and catecholamines. Herein, we sought to delineate specific roles of βarr1 in post-myocardial infarction (MI) HF by testing the effects of βarr1 genetic deletion on normal and post-MI cardiac function and morphology. We studied βarr1 knockout (βarr1KO) mice alongside wild type (WT) controls under normal conditions and after surgical MI. Normal (sham-operated) βarr1KO’s display enhanced βAR-dependent contractility and post-MI βarr1KO’s enhanced overall cardiac function (and βAR-dependent contractility) compared to WT’s. Post-MI βarr1KO’s also show increased survival, and decreased cardiac infarct size, apoptosis, and adverse remodeling, as well as circulating catecholamines & aldosterone, compared to post-MI WT’s. The underlying mechanisms are on one hand improved cardiac βAR signaling and function, as evidenced by increased βAR density and pro-contractile signaling, via reduced cardiac βAR desensitization due to cardiac βarr1 absence, and on the other hand decreased production leading to lower circulating levels of catecholamines & aldosterone due to adrenal βarr1 absence. Thus, βarr1, via both cardiac and adrenal effects, is detrimental for cardiac structure and function and significantly exacerbates post-MI HF.