High plasma concentrations of asymmetric dimethylarginine inhibit ischemic cardioprotection in hypercholesterolemic rats

Abstract

A low concentration of nitric oxide associated with a high concentration of asymmetric dimethylarginine (ADMA) can explain the lack of ischemic cardioprotection observed in the presence of hypercholesterolemia. The objective of the present study was to evaluate the effect of hypercholesterolemia on ischemic pre- and postconditioning and its correlation with plasma concentrations of ADMA. Male Wistar rats (6-8 weeks old) fed a 2% cholesterol diet (n = 21) for 8 weeks were compared to controls (n = 25) and were subjected to experimental myocardial infarction and reperfusion, with ischemic pre- and postconditioning. Total cholesterol and ADMA were measured in plasma before the experimental infarct and the infarct area was quantified. Weight, total cholesterol and plasma ADMA (means ± SE; 1.20 ± 0.06, 1.27 ± 0.08 and 1.20 ± 0.08 vs 0.97 ± 0.04, 0.93 ± 0.05 and 0.97 ± 0.04 µM) were higher in animals on the hypercholesterolemic diet than in controls, respectively. Cardioprotection did not reduce infarct size in the hypercholesterolemic animals (pre: 13.55% and post: 8% compared to 7.95% observed in the group subjected only to ischemia and reperfusion), whereas infarct size was reduced in the animals on a normocholesterolemic diet (pre: 8.25% and post: 6.10% compared to 12.31%). Hypercholesterolemia elevated ADMA and eliminated the cardioprotective effects of ischemic pre- and postconditioning in rats.

Interaction of Risk Factors, Comorbidities, and Comedications with Ischemia/Reperfusion Injury and Cardioprotection by Preconditioning, Postconditioning, and Remote Conditioning

“…The loss of the infarct size limiting effect of ischemic postconditioning has been also confirmed in the last 5 years by several studies in hypercholesterolemic rat (Kupai et al, 2009;Landim et al, 2013;Wu et al, 2014) and rabbit models (Andreadou et al, 2012;Iliodromitis et al, 2010). In the fructose-fed hypertriglyceridemic rat heart, cholesterol lowering by fenofibrate restored ischemic preconditioning-mediated cardioprotection (Babbar et al, 2013).…”

“…Expansion of infarct size in a hyperlipidemic pig model was shown by Osipov et al (2009). The loss of the infarct size limiting effect of ischemic preconditioning (Gorbe et al, 2011;Landim et al, 2013;Babbar et al, 2013;Yadav et al, 2010b;Xu et al, 2013) and late ischemic preconditioning (Yadav et al, 2012) have been shown in different models of diet-induced hyperlipidemia in rats.…”

Effect of hypercholesterolaemia on myocardial function, ischaemia–reperfusion injury and cardioprotection by preconditioning, postconditioning and remote conditioning

“…Since hypercholesterolaemia is linked to oxidative/nitrosative stress in the vasculature and in the myocardium (Szilvassy et al ., ; Giricz et al, ) and to a decreased NO bioavailability, many studies have focused on the role of NO as a potential mechanism of PC's lost effect. A low concentration of NO is associated with a high concentration of asymmetric dimethylarginine (ADMA), and it has been shown that during hypercholesterolaemia the level of ADMA is elevated and the cardioprotective effects of PC are eliminated in rats (Landim et al ., ). The beneficial effects of late PC were shown to be abolished in an in vivo rabbit model of hypercholesterolaemia, due to an impaired up‐regulation of BH4, which is essential for inducible NOS (iNOS) (Tang et al ., ).…”