Diabetic Inhibition of Preconditioning- and Postconditioning-Mediated Myocardial Protection against Ischemia/Reperfusion Injury

Abstract

Ischemic preconditioning (IPC) or postconditioning (Ipost) is proved to efficiently prevent ischemia/reperfusion injuries. Mortality of diabetic patients with acute myocardial infarction was found to be 2–6 folds higher than that of non-diabetic patients with same myocardial infarction, which may be in part due to diabetic inhibition of IPC- and Ipost-mediated protective mechanisms. Both IPC- and Ipost-mediated myocardial protection is predominantly mediated by stimulating PI3K/Akt and associated GSK-3β pathway while diabetes-mediated pathogenic effects are found to be mediated by inhibiting PI3K/Akt and associated GSK-3β pathway. Therefore, this review briefly introduced the general features of IPC- and Ipost-mediated myocardial protection and the general pathogenic effects of diabetes on the myocardium. We have collected experimental evidence that indicates the diabetic inhibition of IPC- and Ipost-mediated myocardial protection. Increasing evidence implies that diabetic inhibition of IPC- and Ipost-mediated myocardial protection may be mediated by inhibiting PI3K/Akt and associated GSK-3β pathway. Therefore any strategy to activate PI3K/Akt and associated GSK-3β pathway to release the diabetic inhibition of both IPC and Ipost-mediated myocardial protection may provide the protective effect against ischemia/reperfusion injuries.

Impaired RISK-GSK3β Pathway is Responsible for Comorbidities by Suppressing the Conditioning Cardioprotection

“…Unlike most kinases, GSK3β is constitutively active and deactivated by phosphorylation. Inactivation of the signaling kinase GSK3β has been shown to be a key event in the intracellular signaling of conditioning (18). In normal state, exogenous drugs and autacoids including adenosine, opioids, and bradykinin induced by conditioning occupy their respective cellular receptor and activate PI3K and RAS-MEK1/2, which cause activation of Akt and ERK1/2, subsequently, the activation of Akt and ERK1/2 further elevate the phosphorylation of GSK3β and finally inhibit mPTP opening at the initial of reperfusion (As shown in Figure 2).…”

“…Treatment of patients with diabetes who have underlying ischemic heart disease is a challenge of the new millennium because of the complex pathophysiology and the poor prognosis of these comorbidities (3,9,18). Therefore, it is a very vigor and vitality field that investigators explore the relationship between cellular mechanisms changes in diabetes and the conditioning cardioprotection (Table 2).…”

“…Previous reviews have elaborated that the diabetes-mediated pathogenic effects are found to be mediated by inhibiting RISK and activating GSK3β pathway which undertakes the responsibility for impairment of ischemic or pharmacological conditioning in diabetic hearts (18). Hyperglycemia and hyper-insulinemia can both activate the GSK3β.…”

Adaptive Phenomenon of Ischemic Postconditioning of the Heart. Perspectives of Clinical Use

“…Сахарный диабет, по данным ряда авторов [24][25][26], встречается у 17-34% больных с острым коронарным синдромом. Принято считать, что данное заболевание существен-но усугубляет течение ОИМ [27]. Этот факт объясняет интерес исследователей к изучению влияния сахарного диабета на эффективность посткондиционирования при экспериментальном инфаркте миокарда.…”

A Simple and Efficient Methodology for the Study of Cardioprotective Drugs in Animal Model of Cardiac Ischemia-Reperfusion

“…The coronary reperfusion therapy constitutes the major therapeutic strategy to salvage the myocardium from tissue injury following prolonged ischemia in AMI patients [3][4][5]. However, the beneficial effects of this therapy are compromised by myocardial injuries caused during coronary reperfusion that subsequently lead to cardiac dysfunctions, including arrhythmias [5][6][7].…”