PPARα activation alleviates damage to the cytoskeleton during acute myocardial ischemia/reperfusion in rats

Abstract

The cytoskeleton serves an important role in maintaining cellular morphology and function, and it is a substrate of calpain during myocardial ischemia/reperfusion (I/R) injury (MIRI). Calpain may be activated by endoplasmic reticulum (ER) stress during MIRI. The activation of peroxisome proliferator-activated receptor α (PPARα) may inhibit ischemia/reperfusion damage by regulating stress reactions. The present study aimed to determine whether the activation of PPARα protects against MIRI-induced cytoskeletal degradation, and investigated the underlying mechanism involved. Wistar rats were pretreated with or without fenofibrate and subjected to left anterior descending coronary artery ligation for 45 min, followed by 120 min of reperfusion. Calpain activity and the expression of PPARα, desmin and ER stress parameters were evaluated. Electrocardiography was performed and cardiac function was evaluated. The ultrastructure was observed under transmission electron microscopy. I/R significantly induced damage to the cytoskeleton in cardiomyocytes and cardiac dysfunction, all of which were improved by PPARα activation. In addition, I/R increased ER stress and calpain activity, which were significantly decreased in fenofibrate-pretreated rat heart tissue. The results suggested that PPARα activation may exert a protective effect against I/R in the myocardium, at least in part via ER stress inhibition. Suppression of ER stress may be an effective therapeutic target for protecting the I/R myocardium.

Targeting PPARα for the Treatment and Understanding of Cardiovascular Diseases

“…Besides the known role of PPARα in the regulation of energy homeostasis, its involvement in modulating the cellular redox response and inflammation in the heart undergoing ischemia/reperfusion (I/R) injury, hypertrophy, and cardiac fibrosis has been documented in recent reports [48,[75][76][77]. Bulhak et al reported that the PPARα agonist WY-14643 protects the myocardium of type 2 diabetic Goto-Kakizaki rats from I/R injury via the activation of the PI3K/Akt and NO pathway [78].…”

Deficiency of peroxisome proliferator-activated receptor α attenuates apoptosis and promotes migration of vascular smooth muscle cells

“…Over the past few decades, PPARα has been explored extensively as therapeutic targets for cardiovascular disorders [ [44] , [45] , [46] ]. Besides its role in the regulation of energy homeostasis, the protective effects of PPARα against myocardial ischemia/reperfusion injury, cardiac fibrosis and hypertrophy, hypertension, vascular inflammation and atherosclerosis have also been documented [ 45 , [47] , [48] , [49] , [50] , [51] ]. However, the molecular mechanisms mediating these effects are still not fully understood.…”

Activation of PPARα by Fenofibrate Attenuates the Effect of Local Heart High Dose Irradiation on the Mouse Cardiac Proteome

“…The beneficial effects of PPAR ligands have been demonstrated on various cardiovascular risk factors [ 42 , 43 , 44 , 45 ]. Agonist activation of PPARα has been shown to protect against acute myocardial ischemia [ 46 ], myocardial remodeling and hypertension [ 47 ], hypertrophy [ 48 ], diabetic cardiomyopathy [ 49 ], atherogenesis [ 50 ] and vascular injury [ 44 ]. The outcome profiles of clinical trials using different PPARα agonists were not consistently similar.…”