Hormetic Responses to Ethanol Ingestion

Ethanol ingestion elicits classic hormetic responses with regard to cardiovascular risk, with intake at low to moderate levels (1–2 units per day) exerting cardioprotective effects in the setting of ischemia/reperfusion (I/R), while consumption at high levels acts to increase the risk for myocardial infarction and stroke. Although polyphenolic antioxidants in red wine were originally thought to account for much of the protection associated with light to moderate drinking, it is now clear that the ethanol component of alcoholic beverages (red and white wine, beer, spirits) also contributes to the development of protected phenotype that limits postischemic tissue injury. From a mechanistic standpoint, early work in this area established that light to moderate ethanol consumption limited the extent of I/R injury by inhibiting platelet function and producing a favorable lipoprotein profile in blood. However, subsequent work has focused on identification of signaling pathways that are activated by ethanol to provoke the appearance of cell survival programs that involve activation of existing effector molecules and the expression of protective gene products. It is hoped that uncovering the signaling pathways invoked by consumption of alcoholic beverages in moderation will allow for identification of new therapeutic approaches that mimic its powerful protective effects, thereby avoiding potential pathologic outcomes and negative behavioral effects that can accompany ethanol ingestion. Small molecule activators of large conductance, calcium-activated potassium channels, and aldehyde dehydrogenase 2 appear to hold particular promise in this regard.