Nicorandil alleviates apoptosis in diabetic cardiomyopathy through PI3K/Akt pathway

Abstract

Nicorandil exerts myocardial protection through its antihypoxia and antioxidant effects. Here, we investigated whether it plays an anti‐apoptotic role in diabetic cardiomyopathy. Sprague‐Dawley rats were fed with high‐fat diet; then single intraperitoneal injection of streptozotocin was performed. Rats with fasting blood glucose (FBG) higher than 11.1 mmol/L were selected as models. Eight weeks after the models were built, rats were treated with nicorandil (7.5 mg/kg day and 15 mg/kg day respectively) for 4 weeks. H9c2 cardiomyocytes were treated with nicorandil and then stimulated with high glucose (33.3 mmol/L). TUNEL assay and level of bcl‐2, bax and caspase‐3 were measured. 5‐HD was used to inhibit nicorandil. Also, PI3K inhibitor (Miltefosine) and mTOR inhibitor (rapamycin) were used to inhibit PI3K/Akt pathway. The results revealed that nicorandil (both 7.5 mg/kg day and 15mg/kg day) treatment can increase the level of NO in the serum and eNOS in the heart of diabetic rats compared with the untreated diabetic group. Nicorandil can also improve relieve cardiac dysfunction and reduce the level of apoptosis. In vitro experiments, nicorandil (100 µmol) can attenuate the level of apoptosis stimulated by high glucose significantly in H9C2 cardiomyocyte compared with the untreated group. The effect of nicorandil on apoptosis was blocked by 5‐HD, and it was accompanied with inhibition of the phosphorylation of PI3K, Akt, eNOS, and mTOR. After inhibition of PI3K/Akt pathway, the protective effect of nicorandil is restrained. These results verified that as a NO donor, nicorandil can also inhibit apoptosis in diabetic cardiomyopathy which is mediated by PI3K/Akt pathway.

Novel Applications of Mesenchymal Stem Cell-Derived Exosomes for Myocardial Infarction Therapeutics

“…Similarly, miR-486-5p from BM-MSC-Exos reduce MI-induced apoptosis by repressing the PTEN pathway and subsequently activating the PI3K/AKT pathway in CMCs [167]. These observations are consistent with other studies investigating the effects of non-exosomal interventions on the PI3K/AKT pathway and apoptosis in the heart [168][169][170].…”

SGLT1 Inhibition Attenuates Apoptosis in Diabetic Cardiomyopathy via the JNK and p38 Pathway

“…Fasting blood glucose (FBG) levels were measured seven days after injection. Rats with FBG ≥ 11.1 mmol/L were considered to be a successful diabetic model ( Ti et al, 2011 ; Wang et al, 2019 ). Then, the diabetic rats were respectively treated with mizagliflozin (SGLT1 inhibitor, gavage at 0.5, 1.0, 1.5 mg/kg), or vehicle (saline, gavage) once daily for 12 weeks.…”

<p>Edaravone and Acetovanillone Upregulate Nrf2 and PI3K/Akt/mTOR Signaling and Prevent Cyclophosphamide Cardiotoxicity in Rats</p>

“…Moreover, the PI3K/Akt/mTOR is another signaling pathway that has been reported to impede cell survival process upon its downregulation. 14,15 Dysregulation of this signaling has also been implicated in cardiomyopathy. 16 Acetovanillone (AV) is a small molecule extracted from Picrorhiza kurroa and has been reported to exert antioxidant, anti-inflammatory and anti-apoptosis activities.…”