A Retinoic Acid -Receptor Agonist Exerts Cardioprotective Effects.

TitleA Retinoic Acid -Receptor Agonist Exerts Cardioprotective Effects.
Publication TypeJournal Article
Year of Publication2018
AuthorsMarino A, Sakamoto T, Tang X-H, Gudas LJ, Levi R
JournalJ Pharmacol Exp Ther
Volume366
Issue2
Pagination314-321
Date Published2018 08
ISSN1521-0103
KeywordsAnimals, Benzoates, Cardiotonic Agents, Mast Cells, Mice, Myocardial Reperfusion Injury, Oxidative Stress, Receptors, Retinoic Acid, Thiazoles
Abstract

We previously discovered that oral treatment with AC261066, a synthetic selective agonist for the retinoic acid -receptor, decreases oxidative stress in the liver, pancreas, and kidney of mice fed a high-fat diet (HFD). Since hyperlipidemic states are causally associated with myocardial ischemia and oxidative stress, we have now investigated the effects of AC261066 in an ex vivo ischemia/reperfusion (I/R) injury model in hearts of two prototypic dysmetabolic mice. We found that a 6-week oral treatment with AC261066 in both genetically hypercholesterolemic (ApoE) and obese (HFD-fed) wild-type mice exerts protective effects when their hearts are subsequently subjected to I/R ex vivo in the absence of added drug. 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 known to elicit the release of MC-derived renin, promoting the activation of the local renin-angiotensin system leading to enhanced 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.

DOI10.1124/jpet.118.250605
Alternate JournalJ. Pharmacol. Exp. Ther.
PubMed ID29907698
PubMed Central IDPMC6041952
Grant ListR01 DK113088 / DK / NIDDK NIH HHS / United States