Hyperglycaemia-induced cardiomyocyte death is mediated via MCP-1 production and induction of a novel zinc-finger protein MCPIP

Abstract

Cardiomyocyte apoptosis contributes to the development of diabetic cardiomyopathy. How the elevated glucose levels associated with diabetes cause cell death is unknown. Here we report that high glucose-induced cardiomyocyte death is mediated via monocyte chemotactic protein-1 (MCP-1) production and induction of a novel zinc-finger protein. H9c2 cardiomyoblasts treated with 28 mmol/L glucose were evaluated for MCP-1 production and induction of the zinc-finger protein, MCP-1-induced protein (MCPIP). Disruptors of MCP-1 interaction with its receptor, CCR2, and knockdown of MCPIP with siRNA were used to determine if MCP-1 and MCPIP mediate glucose-induced cell death. The molecular mechanisms were evaluated by assessing reactive oxygen species (ROS) production, endoplasmic reticulum (ER) stress, and autophagy. Key findings were confirmed in isolated neonatal rat cardiomyocytes. Glucose treatment of H9c2 cardiomyoblasts and isolated cardiomyocytes caused MCP-1 production, MCPIP induction, ROS production, ER stress, autophagy, and cell death. Treatment with CCR2 antagonists and knockdown of MCPIP attenuated glucose-induced ROS production, ER stress, autophagy, and cell death. Inhibition of ROS with 1400 W, tiron, and cerium oxide (CeO(2)) nanoparticles attenuated ER stress, autophagy, and cell death. Specific inhibitors of ER stress and knockdown of IRE-1 attenuated glucose-induced autophagy and cell death. Inhibitors of autophagy and knockdown of beclin-1 attenuated glucose-induced death. Glucose-induced cardiomyocyte death is mediated via MCP-1 production and MCPIP induction, which causes sequential events--ROS production, ER stress, autophagy, and cell death.