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Protection against myocardial ischaemiareperfusion injury by activators of AMP-activated protein kinase (AMPK)

Lasse Solskov

Summary

The PhD dissertation consists of 4 original papers based on animal experimental studies, aiming at investigating the possible cardioprotective (preconditioning) effect of activating the AMPactivated protein kinase (AMPK) enzyme using either high-intensity physical exercise, AICAR (an AMPK-activator) or metformin (anti-diabetic drug and AMPK-activator) and examining the possible changes in myocardial gene expression using Affymetrix GenChips. Furthermore, the aim was to compare the myocardial responsiveness to ischaemia-reperfusion injury and effects of ischaemic preconditioning (IPC) in hearts from depressed Flinders Sensitive Line (FSL) rats and Sprague-Dawley (SD) control rats and to characterize differences in glucose metabolism and insulin sensitivity between the two strains. Study 1 and 2 demonstrated that a single bout of high-intensity exercise, a single treatment with AICAR or a single treatment with metformin activated the AMPK enzyme acutely in the heart and 24 hours later protected the heart against an experimentally induced myocardial infarction by reducing the infarct size by approximately 50% in all three groups compared with controls.
By using Affymetrix GenChips study 3 demonstrated that a single bout of high-intensity exercise, a single treatment with AICAR or a single treatment with metformin resulted in regulation (≥ 2.0-fold) of 147, 305 and 113 genes in the left ventricle in the exercise, AICAR and metformin groups, respectively, mainly involved in cell death, cellular growth and proliferation, gene expression and cancer. There was an overlap of 88 genes between the exercise and AICARtreated rats and an overlap of 6 genes between all three interventions.
Study 4 showed that isolated perfused hearts from FSL rats subjected to 40 minutes of global ischaemia developed significantly larger infarct sizes indicating that these rats are not protected against myocardial ischaemic damage compared to SD control rats. IPC reduced infarct size and improved haemodynamic recovery almost to the same extent in SD and FSL rats. Fasting plasma insulin levels and the HOMA (homeostatic model assessment) index, both markers of insulin resistance, were significantly increased in the FSL rats indicating impaired glucometabolic function in these rats.
To summarize, the studies demonstrate that exercise, AICAR and metformin induce delayed preconditioning in the rat heart by reducing ischaemia-reperfusion injury 24 hours later, through mechanisms that might be mediated by activation of AMPK and by regulation of several identical genes. This opens new and interesting opportunities for the AMPK system as a future therapeutic target in the prevention of ischaemic heart disease. Furthermore, the study conducted in a genetically depressed rat demonstrates that this animal model may be suitable to improve insight into the shared pathophysiological mechanisms that link depression, diabetes and ischaemic heart disease and might contribute to the development of more suitable treatment strategies to reduce the comorbidities of these
diseases.