Dexmedetomidine ameliorates myocardial ischemia-reperfusion injury through regulating FASN-associated cholesterol homeostasis

Dexmedetomidine (Dex) has been used in sedation in intensive care units and as an anesthetic adjunct. However, the mechanism of the protective function of Dex against myocardial ischemia/reperfusion (I/R) injury remains unclear. We applied in vivo rat model as well as in vitro cardiomyocyte models (H9c2 cells and neonatal rat cardiomyocytes, NRCMs) to evaluate the effects of Dex against myocardial I/R injury. In the results, protective effects of Dex were observed in rat heart tissues after I/R injury. Next, transcriptomic sequencing was performed to determine the global change of gene expression, and identified genes related to cholesterol metabolism were significantly upregulated by Dex, where the change of fatty acid synthase (FASN) was the most significant. Furthermore, shRNAs targeting FASN were transfected into H9c2 cells and NRCMs to knock down FASN. By comparing the effects of Dex on both wild type and FASN-knockdown cells under the OGD/R challenge, the protection of Dex was absent in knockdown cells supported by the dataset including the cell viability and apoptosis as well as key gene expressions. Overall, this study systematically evaluates the protective effects of Dex on myocardial I/R injury and provides a better understanding of the role of cholesterol metabolism in the function of Dex.