Irisin and liraglutide combination therapy mitigates myocardial reperfusion injury in obese rats: Role of endoplasmic reticulum stress and apoptosis.

Background: Obesity has become a global health concern, with its prevalence steadily rising across populations. Apart from its well-known association with various metabolic disorders, obesity has also been linked to an increased risk of cardiovascular diseases, including myocardial ischemia-reperfusion (IR) injury. This study aimed to assess how irisin and liraglutide, when used together, impact endoplasmic reticulum (ER) stress-induced apoptosis and PI3K/AKT signaling in obese rats after cardiac IR injury.

Methods: Thirty-six male Sprague-Dawley rats (200-230 g) were fed either a low-fat or high-fat diet for 12 weeks. The obese rats, which were fed a high-fat diet, underwent 30 minutes of left anterior descending coronary artery occlusion followed by 24 hours of reperfusion. Prior to the IR procedure, the obese rats were treated with irisin (0.5 mg/kg/day) and/or liraglutide (0.07 mg/kg/day) for one week. Echocardiographic and hemodynamic parameters, LDH and CK-MB levels, the expression of proteins related to apoptosis (Bax, Bcl-2, cleaved caspase-3) and ER stress (CHOP, GRP78), as well as the phosphorylation of PI3K and AKT, were assessed.

Results: The combination therapy significantly improved cardiac function and reduced LDH and CK-MB levels (P<0.05). Furthermore, this treatment downregulated proteins associated with ER stress, as well as pro-apoptotic markers Bax and cleaved caspase-3, while upregulating the anti-apoptotic protein Bcl-2. Additionally, it enhanced the phosphorylation of PI3K and AKT proteins (P<0.05).

Conclusion: Irisin/liraglutide combination therapy exerted cardioprotective effects against IR injury in obese rats, which were associated with the suppression of ER stress-mediated apoptosis, partly through the enhancement of PI3K/AKT signaling pathway activity.