Polydatin Protects Diabetic Heart against Ischemia‐Reperfusion Injury via Notch1/Hes1‐Mediated Activation of Pten/Akt Signaling

Abstract

Diabetes exacerbates oxidative/nitrative stress during myocardial ischemia-reperfusion (MI/R) injury. Recent studies highlighted the cardioprotective actions of polydatin. However, its effect on diabetic MI/R injury and the underlying mechanisms remain unknown. This work was undertaken to evaluate the effect of polydatin on diabetic MI/R injury with a focus on Notch1/Hes1 signaling and myocardial oxidative/nitrative stress. Streptozotocin- (STZ-) induced diabetic rats were administered with polydatin (20 mg/kg/d) in the absence or presence of DAPT (a γ-secretase inhibitor) or LY294002 (a PI3K/Akt inhibitor) and then subjected to MI/R injury. Polydatin administration preserved cardiac function and reduced myocardial infarct size. Moreover, polydatin ameliorated myocardial oxidative/nitrative stress damage as evidenced by decreased myocardial superoxide generation, malondialdehyde, gp91phox expression, iNOS expression, NO metabolite level, and nitrotyrosine content and increased eNOS phosphorylation. However, these effects were blocked by DAPT administration. DAPT also inhibited the stimulatory effect of polydatin on the Notch1/Hes1-Pten/Akt signaling pathway in a diabetic myocardium. Additionally, LY294002 not only abolished polydatin's antiapoptotic effect but also reversed its inhibitory effect on myocardial oxidative/nitrative stress. Polydatin effectively reduced MI/R injury and improved left ventricular functional recovery under diabetic condition by ameliorating oxidative/nitrative stress damage. Importantly, Notch1/Hes1-mediated activation of Pten/Akt signaling played a crucial role in this process.

Hydromorphine postconditioning protects isolated rat heart against ischemia‐reperfusion injury via activating P13K/Akt/eNOS signaling

“…Our results also showed that hydromorphine exhibited significant effect of increases in the levels of both p‐eNOS and NO in the isolated perfused heart following I/R injury compared with sham group. However, Li MY et al found polydatin protects diabetic rat perfused heart against I/R Injury via increasing the phosphorylation level of eNOS but not increasing NO metabolites, which is paradoxical with our data. Therefore, this inconsistent result suggested that other forms of NOS probably also played a key role in this process, and further research is definitely needed.…”

Analysis of Differentially Expressed Genes in Coronary Artery Disease by Integrated Microarray Analysis

“…SEMA3A was responsible for progression of myocardial infarction [95], but this gene may be associated with pathogenesis of CAD. Genes such as HES1 [96] and NRP1 [97] were important for progression of cardiac ischemia, but these genes may be linked with CAD. Loss of utrophin (UTRN) was involved in the advancement of cardiomyopathy [98], but this gene may be liable for progression of CAD.…”

Notch inhibitor mitigates renal ischemia‑reperfusion injury in diabetic rats

“…Further evidence has indicated that the jagged1/notch signaling pathway serves a critical role in TGF-β2-induced eMT in human rPe cells (31). The notch pathway may precipitate diabetic nephropathy via TGF-β activation (32) and the notch1/Hes1-Pten/akt signaling pathway is involved in a diabetic myocardium (33). notch signaling has been shown to serve a protective role in RI/RI-associated inflammation and apoptosis (34).…”