Hypercholesterolemia Abrogates the Cardioprotection of Ischemic Postconditioning in Isolated Rat Heart: Roles of Glycogen Synthase Kinase-3β and the Mitochondrial Permeability Transition Pore

Abstract

Ischemic postconditioning (IPO) reduces lethal reperfusion injury under normal conditions, but its effectiveness in hypercholesterolemia (HC) is disputed. We measured the cardioprotection of IPO in hypercholesterolemic rats and determined the roles of glycogen synthase kinase-3β (GSK-3β) and the mitochondrial permeability transition pore (mPTP). Isolated rat hearts underwent 30-min global ischemia and 120-min reperfusion. Postconditioning protocol induced six cycles of 10s ischemia and 10s reperfusion at the onset of the reperfusion. Myocardial infarct size was estimated by triphenyltetrazolium chloride staining and cardiomyocyte apoptosis was assessed by TUNEL staining. GSK-3β phosphorylation was measured by immunoblotting. The opening of mPTP was measured by NAD(+) content in myocardium. In normocholesterolemia (NC) groups, infarct size and cardiomyocyte apoptosis were significantly reduced after IPO. These reductions were completely abolished by HC, as evidenced by a similar infarct size and cardiomyocyte apoptosis observed between the IPO-HC and IR (ischemia-reperfusion)-HC groups. GSK-3β phosphorylation was significantly higher in the IPO-NC than the IPO-HC group. In addition, NAD(+) content in myocardium, a marker of mPTP opening, was higher in the IPO-NC group than the IPO-HC group. In conclusion, cardioprotection of IPO is blocked by hypercholesterolemia. This might be due to the impairment of phosphorylation of GSK-3β and attenuation of mPTP opening.

Pharmacological preconditioning and postconditioning with nicorandil attenuates ischemia/reperfusion-induced myocardial necrosis and apoptosis in hypercholesterolemic rats

“…For example, Prasan et al (14) demonstrated that NO production is decreased in the hearts of hypercholesterolemic rabbits during I/R, and Schwemmer et al (29) detected decreased cGMP levels in the hearts of hypercholesterolemic guinea pigs. Furthermore, previous studies have also demonstrated that cardioprotective mechanisms, such as preconditioning and postconditioning, in which the NO/sGC pathway has an important role, are abolished in hyperlipidemia (16)(17)(18). Therefore, we hypothesize that NO donors may have induced cardioprotection against I/R injury in hypercholesterolemic hearts.…”

“…The infarct size was determined as previously described (17). Briefly, after 120 min of reperfusion, the hearts were harvested.…”

“…Previous studies have demonstrated that this vulnerability may be associated with the following: Increased expression of proapoptotic proteins, decreased expression of prosurvival proteins, increased myocardial inflammatory responses and oxidative/nitrative stress, inhibition of nitric oxide (NO) synthesis, and the impaired opening of mitochondrial adenosine triphosphate-sensitive potassium (mitoKATP) channels, in response to myocardial I/R (10-15). Furthermore, hypercholesterolemia abrogates the cardioprotection afforded by IPC, IPost and specific pharmacological agents, such as sevoflurane (16)(17)(18), however the exact underlying mechanisms are yet to be fully elucidated.…”

Postconditioning the Heart: Analysis of Experimental and Clinical Data

“…В 2014 г. китайские кардиологи опубликовали резуль-таты своих экспериментов на изолированных сердцах крыс с гиперхолестеринемией и здоровых особей [9]. Изолированные сердца подвергали глобальной ишемии (30 мин) и реперфузии (2 ч).…”

“…Посткондиционирование способство-вало уменьшению индекса ЗИ/ОР в 2 раза, количества апоптозных кардиомиоцитов -в 3 раза. Гиперхолесте-ринемия устраняла инфаркт-лимитирующий и антиапоп-тотический эффект посткондиционирования [9]. Свои данные авторы подтвердили в том же году еще раз [10]: в опытах на изолированных сердцах крыс с дислипидемией они установили, что добавление в перфузионный раствор фасудила -ингибитора Rho-киназы (Ras homologs -группа белков, родственных белку Ras) -восстанавли-вает инфаркт-лимитирующий эффект адаптации к репер-фузии [10].…”