Activation of Aldehyde Dehydrogenase 2 Reduces Nitroglycerin‐Induced Cardiac Damage

Abstract

INTRODUCTIONNitroglycerin (GTN) tolerance remains a critical barrier to its full benefit of vasodilation. Recent evidence suggests that GTN tolerance is due to inactivation of aldehyde dehydrogenase 2 (ALDH2). We previously showed that activation of ALDH2 by its activator, Alda‐1, reduced cardiac damage after myocardial infarction (MI). Since sustained treatment of GTN inactivates ALDH2, patients on chronic GTN regimen may be at risk of increased cardiac injury after MI. The current study aims to determine whether sustained GTN treatment increases cardiac injury after MI and, if so, whether Alda‐1 can protect from GTN‐induced exacerbation of cardiac damage.METHODSWe used a rat model of MI induced by LAD occlusion. Animals were treated with GTN with or without Alda‐1. Animals were sacrificed at various time points after MI to determine the infarct size and cardiac function. In another study, the effect of Alda‐1 on GTN‐induced inactivation of ALDH2 was determined, in vitro.RESULTSProlonged treatment of GTN reduced ALDH2 activity by 30%, in vivo. GTN caused a two‐fold increase in infarct size and decreased fractional shortening, compared with untreated controls. In contrast, we found that Alda‐1 prevented GTN‐induced ALDH2 inactivation, in vitro. Mechanisms of such inactivation will be discussed. Further, animals given Alda‐1 along with GTN had 40% decrease in infarct size and 15% increase in fractional shortening, indicating that Alda‐1 inhibited GTN‐induced cardiac injury. The data suggested a dilemma that patients under sustained GTN treatment are likely to have more severe cardiac damage after MI. Alda‐1 can be a potential therapeutic to protect these patients from such damage.