Adrenal Beta-Arrestin 1 Inhibition In Vivo Attenuates Post-Myocardial Infarction Progression to Heart Failure and Adverse Remodeling Via Reduction of Circulating Aldosterone Levels

Abstract

Objectives We investigated whether adrenal beta-arrestin 1 (βarr1)-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 (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. 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 βarr1 or inhibit its function via expression of a βarr1 C-terminal-derived peptide fragment. Results 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. Conclusions 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.

Which ARB drug is better for heart failure therapy? Aldosterone suppression holds the answer

“…Consistent with these findings, candesartan and valsartan were also the most potent inhibitors of aldosterone synthesis, whereas losartan and irbesartan were completely incapable of reducing aldosterone synthesis in H295R cells [11] . Importantly, we were able to correlate these in vitro findings from the adreoncortical cells also in vivo, in post-MI rats progressing to HF and overexpressing arr1 specifically in their adrenals [5] . More specifically, circulating plasma aldosterone levels, which are significantly elevated, due to the HF progression, in control vehicle-treated post-MI rats, were found markedly reduced at the end of a 7-day treatment regimen of either valsartan or candesartan, whereas irbesartan, similarly to what we had found previously with losartan [5] , completely failed to reduce the post-MI-associated hyperaldosteronism of these animals, even after a whole week of treatment [12] .…”

“…Importantly, we were able to correlate these in vitro findings from the adreoncortical cells also in vivo, in post-MI rats progressing to HF and overexpressing arr1 specifically in their adrenals [5] . More specifically, circulating plasma aldosterone levels, which are significantly elevated, due to the HF progression, in control vehicle-treated post-MI rats, were found markedly reduced at the end of a 7-day treatment regimen of either valsartan or candesartan, whereas irbesartan, similarly to what we had found previously with losartan [5] , completely failed to reduce the post-MI-associated hyperaldosteronism of these animals, even after a whole week of treatment [12] . This translated into significantly improved cardiac function of the post-MI HF animals, in terms of both ejection fraction and isoproterenol (a standard cardiac positive inotrope)-stimulated contractility by valsartan or candesartan, whereas the failure of irbesartan to suppress circulating aldosterone levels translated into progressively worsening cardiac function in these animals [12] .…”

“…Finally, the 7-day treatment with candesartan significantly reduced post-MI cardiac fibrosis in adrenal arr1-overexpressing rats compared to control vehicle-treated animals, whereas irbesartan treatment for the same time period had no effect [11] . Additionally, the adverse remodeling-associated biomarkers collagen I, atrial natriuretic peptide, and B-type natriuretic peptide, which are markedly elevated by the hyperaldosteronism the adrenal arr1 overexpression causes [5] , were significantly reduced by candesartan after 1 week of treatment, compared to the control vehicle-treated animals and irbesartan treatment for the same time period failed, again, to reduce any of these markers [12] . Taken together, these results indicate that, consistent with their effects on cardiac function and contractility, candesartan significantly halts and/or reverses cardiac adverse remodeling post-MI, despite the presence of the adrenal arr1-driven hyperaldosteronism, whereas irbesartan can improve neither cardiac function, nor adverse remodeling, in the face of adrenal arr1-driven hyperaldosteronism.…”

“…1), which significantly exacerbates post-MI HF [4][5][6] . Of note, the prototypic drug of the ARB class losartan appears ineffective at blocking the adrenal arr1-dependent aldosterone production and hence, at suppressing circulating aldosterone post-MI [5] . This phenomenon (i.e.…”

ARBs and adrenal aldosterone: the beta-arrestin1 connection

“…AT1R is a G protein-coupled receptor (GPCR) that also signals through G protein-independent pathways, a plethora of which are mediated by the scaffolding actions of arrestins (arrs), originally discovered as terminators of GPCR signaling [3] . AngII elicits aldosterone synthesis and secretion via both G proteins and arrs (specifically arr1) [4][5][6] . Of note, the prototypic drug of the ARB class losartan appears ineffective at blocking the adrenal arr1-dependent aldosterone production and hence, at suppressing circulating aldosterone [5] .…”