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摘要
Objectives We investigated whether adrenal beta-arrestin 1 (beta arr1)-mediated aldosterone production plays any role in post-myocardial infarction (MI) heart failure (HF) progression.
Background 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 (AT(1)Rs), G protein-coupled receptors that also signal independently of G proteins. The G protein-independent signaling is mediated by beta arr1 and beta arr2. We recently reported that adrenal beta arr1 promotes AT(1)R-dependent aldosterone production leading to elevated circulating aldosterone levels in vivo.
Methods 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 beta arr1 or inhibit its function via expression of a beta arr1 C-terminal-derived peptide fragment.
Results We found that adrenal beta arr1 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 beta arr1 is inhibited in vivo, which markedly decreases circulating aldosterone after MI. Finally, the prototypic AT(1)R antagonist losartan seems unable to lower this adrenal beta arr1-driven aldosterone elevation.
Conclusions Adrenal beta arr1 inhibition, either directly or with AT1R "biased" antagonists that prevent receptor-beta arr1 coupling, might be of therapeutic value for curbing HF-exacerbating hyperaldosteronism.
- 出版日期2011-1-18
- 单位东南大学
