A Retinoic Acid β 2‐Receptor Agonist Exerts Cardioprotective Effects

Abstract

Metabolic syndrome and hyperlipidemia are causally associated with myocardial ischemia and oxidative stress. We have now investigated the effects of AC261066, a synthetic selective agonist for the retinoic acid β2-receptor, in an ex vivo ischemia/reperfusion (I/R) injury model in hearts using genetically hypercholesterolemic (ApoE-/-) and metabolic syndrome inducing high fat diet (HFD) fed wild-type mouse models. We found that a 6-week oral treatment with AC261066 in both models exerts protective effects when their hearts are subsequently subjected to I/R ex vivo in the absence of AC261066. In ApoE-/- mice this cardioprotection ensued without hyperlipidemic changes. Cardioprotection consisted of attenuation of infarct size, diminution of norepinephrine (NE) spillover, and alleviation of reperfusion arrhythmias. This cardioprotection was associated with a reduction in oxidative stress and mast cell (MC) degranulation. We suggest that the reduction in myocardial injury and adrenergic activation, and the antiarrhythmic effects, result from decreased formation of oxygen radicals and toxic aldehydes that is known to elicit the release of MC-derived renin, promote the local renin-angiotensin system activation that enhances NE release, and reperfusion arrhythmias. Because these beneficial effects of AC261066 occurred at the ex vivo level following oral drug treatment, our data suggest that AC261066 could be viewed as a therapeutic means to reduce I/R injury of the heart, and potentially also be considered in the treatment of other cardiovascular ailments such as chronic arrhythmias and cardiac failure. Currently we are exploring the cardiac protective effects of AC261066 using an in vivo heart failure model.