title: Hyperglycaemia-induced cardiomyocyte death is mediated via MCP-1 production and induction of a novel zinc-finger protein MCPIP.
abstract: OBJECTIVE
  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.
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Burnett School of Biomedical Sciences, College of Medicine, University of Central Florida, Bldg 20, Rm. 136, Orlando, FL 32816, USA.
authors.forename: Craig W
authors.initials: CW
authors.lastname: Younce
authors.forename: Kangkai
authors.initials: K
authors.lastname: Wang
authors.forename: Pappachan E
authors.initials: PE
authors.lastname: Kolattukudy
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D000975:Antioxidants / Q000494:pharmacology; D051017:Apoptosis Regulatory Proteins / Q000235:genetics / Q000378:metabolism; D001343:Autophagy / Q000187:drug effects; D000071186:Beclin-1; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D002460:Cell Line; D018932:Chemokine CCL2 / Q000378:metabolism*; D004721:Endoplasmic Reticulum / Q000378:metabolism; D005947:Glucose / Q000378:metabolism*; D006943:Hyperglycemia / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism; D034622:RNA Interference; D051381:Rats; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species / Q000378:metabolism; D054390:Receptors, CCR2 / Q000037:antagonists & inhibitors / Q000378:metabolism; D013312:Stress, Physiological; D013997:Time Factors; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D016335:Zinc Fingers
chemical_list: D000975:Antioxidants; D051017:Apoptosis Regulatory Proteins; D000071186:Beclin-1; C512829:Becn1 protein, rat; D002352:Carrier Proteins; C491766:Ccl2 protein, rat; C515336:Ccr2 protein, rat; D018932:Chemokine CCL2; D008565:Membrane Proteins; D017382:Reactive Oxygen Species; D054390:Receptors, CCR2; D014157:Transcription Factors; C486557:Ern2 protein, rat; D017346:Protein Serine-Threonine Kinases; D005947:Glucose