Abstract 18660: A Potential Role of TRPM2 Mediated Inflammation in Heart Disease

Background: Inflammation underlies a variety of pathological processes leading to various types of heart disease, including chronic heart failure, arrhythmia, and ischemic cardiomyopathy. The importance of the inflammatory cascade in heart disease has been recognized and thoroughly investigated for the last three decades. However, despite the promising results from experimental studies, attempts to attenuate inflammatory injury in clinical practice have been less successful than expected. A better understanding of the biological process and mechanisms of inflammatory cascade is necessary to identify novel targets for the treatment of inflammatory heart disease. Here we tested the hypothesis that inflammasome activation mediated by the oxidative stress sensitive TRPM2 channels contributes to ischemic cardiomyopathy in I/R mouse model and in human atrial fibrillation (AF). Methods: We used both in vivo ischemia-reperfusion (I/R) mouse model and ex-vivo dissociated fibroblasts from control and AF patients. Heart function of I/R mice was assessed by echocardiograph (ECG) and P-V loop catheter. Results: We found that TRPM2 is highly expressed in cardiac fibroblasts, and that functional TRPM2 channels were readily detected by patch-clamp in cardiac fibroblasts from mouse and human. In I/R mouse heart, TRPM2 was up-regulated by myocardial infarction. In human fibroblasts, the expression of TRPM2 measured by qPCR was much higher in AF versus control patients. We found that the infarct size of TRPM2-knockout mice was much smaller than wide-type (WT) control mice in I/R mouse model. Heart function measured one week after I/R by ECG was also much better in TRPM2-KO mice than WT mice. To understand the mechanism of the protective effects of TRPM2 deletion in heart function of the I/R model, we investigated the formation of inflammasome and found that TRPM2 deletion largely reduced the inflammasome formation in I/R mouse hearts. Conclusions: Fibroblasts from AF patients showed higher expression of TRPM2 detected by qPCR. Moreover, deletion of TRPM2 seems to play an important role in heart protection in the I/R model. Our results suggest that targeting TRPM2 may serve as a potential therapeutic approach for treatment of inflammation associated heart disease.