ß-Arrestin2 Improves Post-Myocardial Infarction Heart Failure via Sarco(endo)plasmic Reticulum Ca2+-ATPase-Dependent Positive Inotropy in Cardiomyocytes.

Heart failure is the leading cause of death in the Western world, and new and innovative treatments are needed. The GPCR (G protein-coupled receptor) adapter proteins ßarr (ß-arrestin)-1 and ßarr-2 are functionally distinct in the heart. ßarr1 is cardiotoxic, decreasing contractility by opposing ß1AR (adrenergic receptor) signaling and promoting apoptosis/inflammation post-myocardial infarction (MI). Conversely, ßarr2 inhibits apoptosis/inflammation post-MI but its effects on cardiac function are not well understood. Herein, we sought to investigate whether ßarr2 actually increases cardiac contractility. Via proteomic investigations in transgenic mouse hearts and in H9c2 rat cardiomyocytes, we have uncovered that ßarr2 directly interacts with SERCA2a (sarco[endo]plasmic reticulum Ca2+-ATPase) in vivo and in vitro in a ß1AR-dependent manner. This interaction causes acute SERCA2a SUMO (small ubiquitin-like modifier)-ylation, increasing SERCA2a activity and thus, cardiac contractility. ßarr1 lacks this effect. Moreover, ßarr2 does not desensitize ß1AR cAMP-dependent procontractile signaling in cardiomyocytes, again contrary to ßarr1. In vivo, post-MI heart failure mice overexpressing cardiac ßarr2 have markedly improved cardiac function, apoptosis, inflammation, and adverse remodeling markers, as well as increased SERCA2a SUMOylation, levels, and activity, compared with control animals. Notably, ßarr2 is capable of ameliorating cardiac function and remodeling post-MI despite not increasing cardiac ßAR number or cAMP levels in vivo. In conclusion, enhancement of cardiac ßarr2 levels/signaling via cardiac-specific gene transfer augments cardiac function safely, that is, while attenuating post-MI remodeling. Thus, cardiac ßarr2 gene transfer might be a novel, safe positive inotropic therapy for both acute and chronic post-MI heart failure.

Suppression of adrenal ßarrestin1-dependent aldosterone production by ARBs: head-to-head comparison.

The known angiotensin II (AngII) physiological effect of aldosterone synthesis and secretion is mediated by either Gq/11 proteins or ßarrestin1 (ßarr1), both of which can couple to its type 1 receptors (AT1Rs), present in adrenocortical zona glomerulosa (AZG) cell membranes. In the present study, we examined the relative potencies of all the currently used in the clinic AT1R antagonist drugs (angiotensin receptor blockers, ARBs, or sartans) at preventing activation of these two signaling mediators (G proteins and ßarrs) at the AngII-bound AT1R and, consequently, at suppression of aldosterone in vitro. All ARBs were found to be potent inhibitors of G protein activation at the AT1R. However, candesartan and valsartan were the most potent at blocking AngII-induced ßarr activation at this receptor, among the tetrazolo-biphenyl-methyl derivatives, translating into excellent efficacies at aldosterone suppression in H295R cells. Conversely, irbesartan and losartan were largely G protein-selective inhibitors at the AT1R, with very low potency towards ßarr inhibition. As a result, they were very weak suppressors of ßarr1-dependent aldosterone production in H295R cells. These findings provide important pharmacological insights into the drug class of ARBs and medicinal chemistry insights for future drug development in the field of AngII antagonism.

Negative impact of ß-arrestin-1 on post-myocardial infarction heart failure via cardiac and adrenal-dependent neurohormonal mechanisms.

ß-Arrestin (ßarr)-1 and ß-arrestin-2 (ßarrs) are universal G-protein-coupled receptor adapter proteins that negatively regulate cardiac ß-adrenergic receptor (ßAR) function via ßAR desensitization and downregulation. In addition, they mediate G-protein-independent ßAR signaling, which might be beneficial, for example, antiapoptotic, for the heart. However, the specific role(s) of each ßarr isoform in cardiac ßAR dysfunction, the molecular hallmark of chronic heart failure (HF), remains unknown. Furthermore, adrenal ßarr1 exacerbates HF by chronically enhancing adrenal production and hence circulating levels of aldosterone and catecholamines. Herein, we sought to delineate specific roles of ßarr1 in post-myocardial infarction (MI) HF by testing the effects of ßarr1 genetic deletion on normal and post-MI cardiac function and morphology. We studied ßarr1 knockout (ßarr1KO) mice alongside wild-type controls under normal conditions and after surgical MI. Normal (sham-operated) ßarr1KO mice display enhanced ßAR-dependent contractility and post-MI ßarr1KO mice enhanced overall cardiac function (and ßAR-dependent contractility) compared with wild type. Post-MI ßarr1KO mice also show increased survival and decreased cardiac infarct size, apoptosis, and adverse remodeling, as well as circulating catecholamines and aldosterone, compared with post-MI wild type. The underlying mechanisms, on one hand, improved cardiac ßAR signaling and function, as evidenced by increased ßAR density and procontractile signaling, via reduced cardiac ßAR desensitization because of cardiac ßarr1 absence, and, on the other hand, decreased production leading to lower circulating levels of catecholamines and aldosterone because of adrenal ßarr1 absence. Thus, ßarr1, via both cardiac and adrenal effects, is detrimental for cardiac structure and function and significantly exacerbates post-MI HF.

Current and future G protein-coupled receptor signaling targets for heart failure therapy.

Although there have been significant advances in the therapy of heart failure in recent decades, such as the introduction of ß-blockers and antagonists of the renin-angiotensin-aldosterone system, this devastating disease still carries tremendous morbidity and mortality in the western world. G protein-coupled receptors, such as ß-adrenergic and angiotensin II receptors, located in the membranes of all three major cardiac cell types, ie, myocytes, fibroblasts, and endothelial cells, play crucial roles in regulation of cardiac function in health and disease. Their importance is reflected by the fact that, collectively, they represent the direct targets of over one-third of the currently approved cardiovascular drugs used in clinical practice. Over the past few decades, advances in elucidation of the signaling pathways they elicit, specifically in the heart, have led to identification of an increasing number of new molecular targets for heart failure therapy. Here, we review these possible targets for heart failure therapy that have emerged from studies of cardiac G protein-coupled receptor signaling in health and disease, with a particular focus on the main cardiac G protein-coupled receptor types, ie, the ß-adrenergic and the angiotensin II type 1 receptors. We also highlight key issues that need to be addressed to improve the chances of success of novel therapies directed against these targets.