Hypercholesterolemia Abrogates Late Preconditioning via a Tetrahydrobiopterin-Dependent Mechanism in Conscious Rabbits

Abstract

Background-Although the late phase of ischemic preconditioning (PC) is known to confer cardioprotection in healthy animal models, it is unknown whether this phenomenon exists in the presence of hypercholesterolemia. The goal of this study was to determine whether the infarct-sparing effect of late PC is affected by hypercholesterolemia and, if so, whether a tetrahydrobiopterin (BH 4 )-dependent mechanism is responsible for the loss of late PC. Methods and Results-Conscious rabbits fed a normal diet or a 1% cholesterol diet for 6 weeks were subjected to ischemic PC (six 4-minute coronary occlusion/4-minute reperfusion cycles) and, 24 hours later, underwent a 30-minute occlusion followed by 3 days of reperfusion. A total of 125 rabbits were used. In normocholesterolemic rabbits, ischemic PC reduced infarct size, an effect that was abrogated by administration of the BH 4 synthesis inhibitor N-acetylserotonin (15 mg/kg IV) before the 30-minute occlusion. In hypercholesterolemic rabbits, however, ischemic PC failed to reduce infarct size. Myocardial BH 4 levels in the ischemic zone increased 24 hours after ischemic PC in normocholesterolemic rabbits but not in hypercholesterolemic rabbits. In addition, in normocholesterolemic rabbits, pretreatment with N-acetylserotonin completely abolished the ischemic PC-induced increase in myocardial BH 4 levels. Conclusions-This study demonstrates that (1) hypercholesterolemia abrogates both the infarct-sparing effect of late PC and the concomitant upregulation of myocardial BH 4 , and (2)

Interaction of Cardiovascular Risk Factors with Myocardial Ischemia/Reperfusion Injury, Preconditioning, and Postconditioning

“…However, the bacterial endotoxin analog monophosphoryl lipid A-induced late protection in the same rabbit model remained unaffected by experimental hyperlipidemia and atherosclerosis (Szilvassy et al, 1998). The loss of the infarct size-limiting effect of late preconditioning in another conscious rabbit model of coronary occlusion and reperfusion was shown by Tang et al (2005). The loss of NO donor-induced late preconditioning was shown in the same rabbit model by the same group (Tang et al, 2004).…”

“…A decrease in cardiac NO bioavailability due to increased nitrosative stress (Hoshida et al, 1996;Ferdinandy et al, 1997;Csonka et al, 2001;Tang et al, 2005; CARDIOPROTECTION AND RISK FACTORS for reviews, see Ferdinandy and Schulz, 2003;Pacher et al, 2007) and resulting activation of matrix metalloproteinases increased ecto-5Ј-nucleotidase activity (Ueda et al, 1999), as well as enhanced apoptotic cell death via the caspase-1 cascade , have been shown to contribute to increased ischemia/reperfusion injury and loss of classic preconditioning in hyperlipidemic animal models. Interestingly, inhibition of the mevalonate pathway by hyperlipidemia has been also described as a possible mechanism of the lost cardioprotection because mevalonate restored the effect of preconditioning on postischemic myocardial function and lactate dehydrogenase release in hyperlipidemic rats .…”

Cardioprotection by postconditioning in conscious rats is limited to coronary occlusions <45 min

“…For studies of ischemic preconditioning, initially we used a protocol of six 4-min occlusion/4-min reperfusion cycles [the same protocol we have used in our previous studies in conscious rabbits (20,23,25) and in open-chest mice (9, 10)]. We tested this protocol in four conscious rats and found that all four animals developed ventricular fibrillation upon reperfusion after the first 4-min coronary occlusion.…”

Pathophysiology of myocardial reperfusion injury: preconditioning, postconditioning, and translational aspects of protective measures

“…This also applies to late preconditioning (199) and postconditioning (73). In fact, the same rabbit in the ischemia-reperfusion model was used to show the loss of the infarct limitation in response to late preconditioning (204).…”