A Retinoic Acid β2-Receptor Agonist Exerts Cardioprotective Effects. Academic Article uri icon

Overview

abstract

  • We previously discovered that oral treatment with AC261066, a synthetic selective agonist for the retinoic acid β2-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.

publication date

  • June 15, 2018

Research

keywords

  • Benzoates
  • Cardiotonic Agents
  • Receptors, Retinoic Acid
  • Thiazoles

Identity

PubMed Central ID

  • PMC6041952

Scopus Document Identifier

  • 85050385528

Digital Object Identifier (DOI)

  • 10.1124/jpet.118.250605

PubMed ID

  • 29907698

Additional Document Info

volume

  • 366

issue

  • 2