Abstract 14400: Manipulating Myocardial Wnt Signalling For Post-Ischemic Myocardial Protection
Myocardial injury due to ischemia-reperfusion (I-R) damage remains a major clinical challenge. Currently the pathogenesis of I-R injury continues to be debated and to date no clinically proven approaches have been developed to lessen I-R injury. In this study we explored the novel hypothesis that activation of the Wnt pathway plays a pivotal role in both cellular and mitochondrial dysfunction during I-R and that its inhibition may provide a novel target for therapeutic interventions. We found a significant (p<0.05) increase in Wnt3a mRNA expression in isolated mouse cardiomyocytes following 3hr hypoxia-2hr reoxygenation (223 ± 44%) and in-vivo following I-R (840 ± 450%) compared to sham controls. Uniquely, we observed that 3nM Wnt3a treatment significantly reduces mitochondrial function assessed by basal respiration, ATP turnover, maximal respiratory capacity, fatty acid oxidation and glucose oxidation in isolated mouse cardiomyocytes using a Seahorse XF analyser (all p<0.001). This was accompanied with a significant increase in cardiomyocyte cell death (LDH release, 0.118 ± 0.005 vs 0.05 ± 0.002AU, p<0.05) after 30min Wnt3 suggesting the increase in Wnt3a expression observed following I-R is detrimental to cardiomyocytes. To investigate the potential therapeutic role of Wnt inhibition on cardiomyocyte response to I-R injury, we examined the effect of sFRP2 which binds Wnt3a on cardiomyocytes exposed to hypoxia-reoxygenation. sFRP2 (100nM) significantly preserved mitochondrial membrane potential (90 ± 2 vs 76 ± 2% of normoxic controls, p<0.001) and reduced both ROS production (90 ± 16 vs 170 ± 12%, p<0.05) and cell death (0.04 ± 0.005 vs 0.09 ± 0.008AU, p<0.001) following hypoxia-reoxygenation. This was also associated with a significant (p<0.01) improvement in fatty acid oxidation post hypoxia-reoxygenation. In addition, sFRP2 co-treatment significantly reduced LDH release in Wnt3a treated cardiomyocytes (0.079 ± 0.01 vs 0.118 ± 0.005AU, p<0.05). Taken together, these data strongly point to a role for the Wnt pathway in the pathogenesis of myocardial I-R injury, integrated by an alteration in mitochondrial metabolism. Inhibition of the Wnt pathway during I-R may improve outcome after MI and prevent the transition of MI patients to heart failure.
- © 2011 by American Heart Association, Inc.