KCNJ11 Downregulation Stimulates Cardiac Cell Apoptosis in Myocarditis

One of the inflammatory heart diseases, viz. acute myocarditis, occurs due to cardiac cell death. However, the molecular mechanism underlying cell death remains largely unexplored. In this study, we report that the down-regulation of KCNJ11, a central subunit of the ATP-sensitive potassium (KATP) channel plays a key role in the reduction of blood glucose, and is involved in apoptosis of cardiac cells. Using proteomics analysis of experimental autoimmune myocarditis (EAM), we show that the KCNJ11 level marked by decreased, whereas Camk2a expression increased significantly in EAM tissues by 16 and 20 days, compared to control tissues. Using 1H-MAS NMR we also show that glucose levels were slightly elevated in EAM tissues. In vitro assays using H9c2 cardiac cells revealed that both lipopolysaccharide (LPS) and high glucose treatment decreased cell viability, in which toxicity was attenuated by treatment with KATP pharmacological openers, but not by the KATP blockers (Gli and 5-HD). Apoptosis induced by LPS or high glucose treatment was suppressed by Ca²⁺ chelator (BAPTA-AM) treatment. We found that KCNJ11 levels had decreased in cardiac cells by LPS or high glucose treatment, and siRNA-mediated knockdown of KCNJ11 expression further stimulated the LPS- or high glucose-induced apoptosis. Together, our results demonstrate first that KCNJ11 is down-regulated under inflammation and high glucose conditions and its inactivation facilitates cardiac cell apoptosis. We assume that down-regulation of KCNJ11 has an effect on the development of myocarditis.