Department of Pharmaceutical Sciences, Nova Southeastern University College of Pharmacy, Fort Lauderdale, Florida 33328, USA.
J Am Coll Cardiol. 2011 Jan 18;57(3):356-65. doi: 10.1016/j.jacc.2010.08.635.
We investigated whether adrenal beta-arrestin 1 (βarr1)-mediated aldosterone production plays any role in post-myocardial infarction (MI) heart failure (HF) progression.
Heart failure represents 1 of the most significant health problems worldwide, and new and innovative treatments are needed. Aldosterone contributes significantly to HF progression after MI by accelerating adverse cardiac remodeling and ventricular dysfunction. It is produced by the adrenal cortex after angiotensin II activation of angiotensin II type 1 receptors (AT₁Rs), G protein-coupled receptors that also signal independently of G proteins. The G protein-independent signaling is mediated by βarr1 and βarr2. We recently reported that adrenal βarr1 promotes AT₁R-dependent aldosterone production leading to elevated circulating aldosterone levels in vivo.
Adrenal-targeted, adenoviral-mediated gene delivery in vivo in 2-week post-MI rats, a time point around which circulating aldosterone significantly increases to accelerate HF progression, was performed to either increase the expression of adrenal βarr1 or inhibit its function via expression of a βarr1 C-terminal-derived peptide fragment.
We found that adrenal βarr1 overexpression promotes aldosterone elevation after MI, resulting in accelerated cardiac adverse remodeling and deterioration of ventricular function. Importantly, these detrimental effects of aldosterone are prevented when adrenal βarr1 is inhibited in vivo, which markedly decreases circulating aldosterone after MI. Finally, the prototypic AT₁R antagonist losartan seems unable to lower this adrenal βarr1-driven aldosterone elevation.
Adrenal βarr1 inhibition, either directly or with AT₁R "biased" antagonists that prevent receptor-βarr1 coupling, might be of therapeutic value for curbing HF-exacerbating hyperaldosteronism.
我们研究了肾上腺β-arrestin 1（βarr1）介导的醛固酮产生是否在心肌梗死后心力衰竭（HF）进展中起作用。
心力衰竭是全球最重要的健康问题之一，需要新的创新治疗方法。醛固酮通过加速不良心脏重构和心室功能障碍，在心肌梗死后HF 进展中起重要作用。它是由肾上腺皮质在血管紧张素 II 激活血管紧张素 II 型 1 受体（AT₁Rs）后产生的，G 蛋白偶联受体也可以独立于 G 蛋白信号转导。非 G 蛋白依赖性信号转导由βarr1 和βarr2 介导。我们最近报道，肾上腺βarr1 促进 AT₁R 依赖性醛固酮产生，导致体内循环醛固酮水平升高。
在心肌梗死后 2 周的大鼠体内进行肾上腺靶向、腺病毒介导的基因传递，此时循环醛固酮水平显著升高，加速 HF 进展，以增加肾上腺βarr1 的表达或通过表达βarr1 C 端衍生肽片段抑制其功能。
我们发现，肾上腺βarr1 过表达促进 MI 后醛固酮升高，导致心脏不良重构加速和心室功能恶化。重要的是，当体内抑制肾上腺βarr1 时，这些醛固酮的有害作用被预防，这显著降低了 MI 后循环中的醛固酮。最后，原型 AT₁R 拮抗剂氯沙坦似乎无法降低这种由肾上腺βarr1 驱动的醛固酮升高。
肾上腺βarr1 抑制，无论是直接抑制还是使用阻止受体-βarr1 偶联的 AT₁R“偏向”拮抗剂，对于抑制 HF 加重的高醛固酮血症可能具有治疗价值。
