JNK exacerbates ischemia/reperfusion injury in hyperglycemic subjects.

Summary

Principal Investigator: Keith Webster
Abstract: The mean time to reperfusion of acute myocardial infarction patients in the USA is 3-4h. The metabolic activity within the ischemic tissue over this period is a major determinant of outcome and is critically influenced by the glycemic and insulin responsive status of the subject. Inadequate glucose-stimulated insulin production and/or insulin resistance of muscle and liver cause hyperglycemia. We hypothesize that the exacerbated injury that accompanies myocardial ischemia/reperfusion in hyperglycemic subjects is at least in part the consequence of an early switch in the function of c-Jun-N-terminal kinase (JNK) from pro-survival to pro-death. We previously described an energy-dependent switch in the function of JNK in cultured cardiac myocytes. The switch occurred when cardiac myocyte ATP level fell by below 50%, a condition that sensitized myocytes to oxidative stress, and coincided with increased phosphorylation of the insulin receptor substrate-1 (IRS-1) on the inhibitory serine-307. We have now confirmed that the switch also operates in vivo when the myocardium is subjected to ischemia/reperfusion and encounters similar metabolic stress. The in vivo effect is dramatic, JNK inhibition during prolonged ischemia reduced both apoptosis and infarction by ~50%, but the same inhibition imposed on a short ischemic episode increased apoptosis >3-fold and infarct >2-fold. Because >50% of injury caused by severe ischemia/reperfusion is regulated by JNK, the switch is potentially a major contributor to the outcome of AMI. In this revised application we will determine the degree to which the etiology of hyperglycemia affects JNK metabolic switching, characterize the metabolic signals that mediate switching and determine the death/survival pathways that are affected. In Aim 1 we will determine infarction and remodeling over time by high-definition echocardiography and micro-MRI. This will be implemented in 3 models of hyperglycemia: (i) db/db mice with monogenetic susceptibility to obesity and insulin resistance. (ii) NONcNZO10 mice with polygenic susceptibility to obesity and insulin resistance. (iii) Wild type mice infused with lipid to induce insulin resistance and hyperglycemia. In Aim 2 we will use advanced imaging techniques including micro-NMR/MRI to determine the precise metabolic parameters that regulate JNK switching in normal and hyperglycemic hearts subjected to ischemia/reperfusion. In Aim 3 we will define the death pathways that are affected by the JNK switch and the long-term effects on remodeling and gene expression in the affected region of the myocardium. PUBLIC HEALTH RELEVANCE: Fasting hyperglycemia is associated with increased myocardial infarction in both animal models and patients. Fasting hyperglycemia is also associated with insulin resistance. The mechanism for the poor outcome of hyperglycemic patients to acute myocardial infarction is not known. Here we present a new hypothesis where stress kinases are activated specifically in hyperglycemic patients undergoing AMI and cause poor outcome. Experiments are proposed to test this hypothesis in mouse models. If our hypothesis is correct we will described the molecular basis for this an begin to develop new approaches for treatment.
Funding Period: ----------------2009 - ---------------2011-
more information: NIH RePORT

Top Publications

  1. pmc Extracellular calcium increases CXCR4 expression on bone marrow-derived cells and enhances pro-angiogenesis therapy
    Quiling Wu
    Vascular Biology Institute, University of Miami, Miller School of Medicine, Miami, FL 33136, USA
    J Cell Mol Med 13:3764-73. 2009
  2. pmc In vivo upregulation of nitric oxide synthases in healthy rats
    Heng Wu
    Divisions of Neonatology, Mount Sinai Medical Center, Miami Beach, FL 33140, USA
    Nitric Oxide 21:63-8. 2009
  3. pmc Methionine sulfoxide reductase A (MsrA) protects cultured mouse embryonic stem cells from H2O2-mediated oxidative stress
    Chi Zhang
    Department of Biomedical Science, Florida Atlantic University, Boca Raton, Florida 33431, USA
    J Cell Biochem 111:94-103. 2010
  4. pmc Influence of diet on visceral adipose remodeling in NONcNZO10 mice with polygenic susceptibility for type 2 diabetes
    Nikhil C Adi
    Department of Molecular and Cellular Pharmacology, Miller School of Medicine, University of Miami, Miami, Florida, USA
    Obesity (Silver Spring) 20:2142-6. 2012
  5. pmc c-Jun N-terminal kinase (JNK-1) confers protection against brief but not extended ischemia during acute myocardial infarction
    Jianqin Wei
    Department of Molecular and Cellular Pharmacology, Vascular Biology Institute, University of Miami Miller School of Medicine, Miami, Florida 33136, USA
    J Biol Chem 286:13995-4006. 2011
  6. pmc An essential role for diet in exercise-mediated protection against dyslipidemia, inflammation and atherosclerosis in ApoE⁻/⁻ mice
    Liliana Cesar
    Department of Molecular and Cellular Pharmacology and the Vascular Biology Institute, University of Miami Miller School of Medicine, Miami, Florida, United States of America
    PLoS ONE 6:e17263. 2011
  7. pmc Impaired CXCR4 expression and cell engraftment of bone marrow-derived cells from aged atherogenic mice
    Qiyuan Xu
    Department of Cardiology, 2nd Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China
    Atherosclerosis 219:92-9. 2011

Scientific Experts

  • Keith Webster
  • Liliana Cesar
  • Jennipher Adi
  • Paul Kurlansky
  • Hong Yu
  • Nikhil C Adi
  • Nikhil Adi
  • Qiyuan Xu
  • Jianqin Wei
  • Chi Zhang
  • Heng Wu
  • Quiling Wu
  • Jennipher N Adi
  • Arthur S Agatston
  • Jinlin He
  • Jian An Wang
  • Pascal J Goldschmidt-Clermont
  • Ines Chopra
  • Mingsheng Zhou
  • Huilan Wang
  • Qi Ma
  • Hui Fang Li
  • Christopher J Dougherty
  • Arthur Agatston
  • Roberto Vazquez-Padron
  • Weiwen Wang
  • Samuel Vasallo Suarez
  • Yuanyuan Jia
  • Pingping Jia
  • Mohan Achary
  • Xupei Huang
  • Herbert Weissbach
  • Sharon L Lemanski
  • Larry F Lemanski
  • Ying Jin
  • Eton D Darwin
  • Hongwei Shao
  • Bing Yang
  • Jorge Bassuk
  • Arkady Uryash
  • Jiahui Li
  • Jaqueline Arias
  • Jie Li
  • Jose A Adams

Detail Information

Publications8

  1. pmc Extracellular calcium increases CXCR4 expression on bone marrow-derived cells and enhances pro-angiogenesis therapy
    Quiling Wu
    Vascular Biology Institute, University of Miami, Miller School of Medicine, Miami, FL 33136, USA
    J Cell Mol Med 13:3764-73. 2009
    ..Our results identify calcium as a positive regulator of CXCR4 expression that promotes stem cell mobilization, homing and therapy...
  2. pmc In vivo upregulation of nitric oxide synthases in healthy rats
    Heng Wu
    Divisions of Neonatology, Mount Sinai Medical Center, Miami Beach, FL 33140, USA
    Nitric Oxide 21:63-8. 2009
    ..Such upregulation of eNOS and nNOS was still evident 24h after pGz. Further studies are needed to understand the biochemical and biomechanical signal transduction pathway for the observed NOS phenotype changed induced by pGz...
  3. pmc Methionine sulfoxide reductase A (MsrA) protects cultured mouse embryonic stem cells from H2O2-mediated oxidative stress
    Chi Zhang
    Department of Biomedical Science, Florida Atlantic University, Boca Raton, Florida 33431, USA
    J Cell Biochem 111:94-103. 2010
    ..Our results indicate that MsrA plays an important role in cellular defenses against oxidative stress in ESCs. Msr genes may provide a new target in stem cells to increase their survivability during the therapeutic applications...
  4. pmc Influence of diet on visceral adipose remodeling in NONcNZO10 mice with polygenic susceptibility for type 2 diabetes
    Nikhil C Adi
    Department of Molecular and Cellular Pharmacology, Miller School of Medicine, University of Miami, Miami, Florida, USA
    Obesity (Silver Spring) 20:2142-6. 2012
    ..Two-way ANOVA confirmed strongly interactive roles of diet and genetics on fat deposition and progression of type 2 diabetes in this polygenic mouse model...
  5. pmc c-Jun N-terminal kinase (JNK-1) confers protection against brief but not extended ischemia during acute myocardial infarction
    Jianqin Wei
    Department of Molecular and Cellular Pharmacology, Vascular Biology Institute, University of Miami Miller School of Medicine, Miami, Florida 33136, USA
    J Biol Chem 286:13995-4006. 2011
    ..The studies define a novel role for JNK-1 as a conditional survival kinase that protects the heart against brief but not protracted ischemia...
  6. pmc An essential role for diet in exercise-mediated protection against dyslipidemia, inflammation and atherosclerosis in ApoE⁻/⁻ mice
    Liliana Cesar
    Department of Molecular and Cellular Pharmacology and the Vascular Biology Institute, University of Miami Miller School of Medicine, Miami, Florida, United States of America
    PLoS ONE 6:e17263. 2011
    ..Using atherosclerosis-prone ApoE-null mice we sought to determine whether the benefits of exercise for arterial disease are dependent on the food source of the additional calories...
  7. pmc Impaired CXCR4 expression and cell engraftment of bone marrow-derived cells from aged atherogenic mice
    Qiyuan Xu
    Department of Cardiology, 2nd Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China
    Atherosclerosis 219:92-9. 2011
    ..To determine the impact of aging and atherosclerotic disease on the chemotaxic activity of bone marrow derived cells (BMCs), we examined CXCR4 surface expression on BMCs from aged and atherosclerotic mice...