Myocardial Ischemia/Reperfusion Injury and Infarct Size in Vivo

The c-Jun NH(2)-terminal kinase (JNK) pathway of the mitogen-activated protein kinase (MAPK) signaling cascade regulates cell function and survival after stress stimulation. Equally robust studies reported dichotomous results suggesting both protective and detrimental effects of JNK during myocardial ischemia-reperfusion (I/R). The lack of a highly specific JNK inhibitor contributed to this controversy. We recently developed a cell-penetrating, protease-resistant peptide inhibitor of JNK, d-JNKI-1. Here we report on the effects of d-JNKI-1 in myocardial I/R. d-JNKI-1 was tested in isolated-perfused adult rat hearts. Increased activation of JNK, p38-MAPK, and extracellular signal-regulated kinase-1/2 (ERK1/2), as assessed by kinase assays and Western blotting, occurred during I/R. d-JNKI-1 delivered before onset of ischemia prevented the increase in JNK activity while not affecting ERK1/2 and p38-MAPK activation. JNK inhibition reduced ischemic injury, as manifested by increased time to contracture (P < 0.05) and decreased left ventricular end-diastolic pressure during ischemia (P < 0.01), and enhanced posthypoxic recovery of systolic and diastolic function (P < 0.01). d-JNKI-1 reduced mitochondrial cytochrome-c release, caspase-3 activation, and the number of apoptotic cells determined by terminal deoxynucleotidyltransferase-mediated dUTP nick-end labeling (P < 0.05), indicating suppression of the mitochondrial machinery of apoptosis. d-JNKI-1 delivered at the time of reperfusion did not improve functional recovery but still prevented apoptosis. In vivo, d-JNKI-1 reduced infarct size after coronary artery occlusion and reperfusion by approximately 50% (P < 0.01). In conclusion, d-JNKI-1 is an important compound that can be used in preclinical models to investigate the role of JNK signaling in vivo. Inhibition of JNK during I/R is cardioprotective in anesthetized rats in vivo.

[1]  J. Comella,et al.  Switch from Caspase-dependent to Caspase-independent Death during Heart Development , 2006, Journal of Biological Chemistry.

[2]  L. Kappenberger,et al.  Brief reoxygenation episodes during chronic hypoxia enhance posthypoxic recovery of LV function , 2006, Basic Research in Cardiology.

[3]  Yow-Ming C Wang,et al.  c-Jun N-Terminal Kinases Mediate Reactivation of Akt and Cardiomyocyte Survival After Hypoxic Injury In Vitro and In Vivo , 2005, Circulation research.

[4]  T. Hewett,et al.  Genetic Inhibition or Activation of JNK1/2 Protects the Myocardium from Ischemia-Reperfusion-induced Cell Death in Vivo* , 2005, Journal of Biological Chemistry.

[5]  K. Webster,et al.  Mitochondrial signals initiate the activation of c‐Jun N‐terminal kinase (JNK) by hypoxia‐reoxygenation , 2004, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[6]  C. Niesler,et al.  p38 and JNK have distinct regulatory functions on the development of apoptosis during simulated ischaemia and reperfusion in neonatal cardiomyocytes , 2004, Basic Research in Cardiology.

[7]  F. de Ribaupierre,et al.  A Peptide Inhibitor of C-jun N-terminal Kinase Protects against Both Aminoglycoside and Acoustic Trauma-induced Auditory Hair Cell Death and Hearing Loss , 2022 .

[8]  A. Vercelli,et al.  A peptide inhibitor of c-Jun N-terminal kinase protects against excitotoxicity and cerebral ischemia , 2003, Nature Medicine.

[9]  D. Sawyer,et al.  H(2)O(2) regulates cardiac myocyte phenotype via concentration-dependent activation of distinct kinase pathways. , 2003, Journal of molecular and cellular cardiology.

[10]  R. Lauro,et al.  Characterization of apoptosis signal transduction pathways in HL‐5 cardiomyocytes exposed to ischemia/reperfusion oxidative stress model , 2003, Journal of cellular physiology.

[11]  D. Sawyer,et al.  &bgr;-Adrenergic Receptor–Stimulated Apoptosis in Cardiac Myocytes Is Mediated by Reactive Oxygen Species/c-Jun NH2-Terminal Kinase–Dependent Activation of the Mitochondrial Pathway , 2003, Circulation research.

[12]  M. Bogoyevitch,et al.  Identification of the Critical Features of a Small Peptide Inhibitor of JNK Activity* , 2002, The Journal of Biological Chemistry.

[13]  P. Kang,et al.  Direct Activation of Mitochondrial Apoptosis Machinery by c-Jun N-terminal Kinase in Adult Cardiac Myocytes* , 2002, The Journal of Biological Chemistry.

[14]  K. Webster,et al.  Activation of c-Jun N-terminal kinase promotes survival of cardiac myocytes after oxidative stress. , 2002, The Biochemical journal.

[15]  R. Fryer,et al.  Stress-activated protein kinase phosphorylation during cardioprotection in the ischemic myocardium. , 2001, American journal of physiology. Heart and circulatory physiology.

[16]  B. Monia,et al.  Inhibition of c-Jun N-terminal kinase 1, but not c-Jun N-terminal kinase 2, suppresses apoptosis induced by ischemia/reoxygenation in rat cardiac myocytes. , 2001, Molecular pharmacology.

[17]  K. Webster,et al.  Cytoprotection by Jun Kinase During Nitric Oxide–Induced Cardiac Myocyte Apoptosis , 2001, Circulation research.

[18]  P. Pratt,et al.  Differential activation of extracellular signal regulated kinase isoforms in preconditioning and opioid-induced cardioprotection. , 2001, The Journal of pharmacology and experimental therapeutics.

[19]  R. Weiss,et al.  Antioxidant therapy attenuates JNK activation and apoptosis in the remote noninfarcted myocardium after large myocardial infarction. , 2001, Biochemical and biophysical research communications.

[20]  D. Schorderet,et al.  Cell-permeable peptide inhibitors of JNK: novel blockers of beta-cell death. , 2001, Diabetes.

[21]  D. Schorderet,et al.  Cell-Permeable Peptide Inhibitors of JNK: Novel Blockers of β-Cell Death , 2001 .

[22]  T. Yue,et al.  Inhibition of extracellular signal-regulated kinase enhances Ischemia/Reoxygenation-induced apoptosis in cultured cardiac myocytes and exaggerates reperfusion injury in isolated perfused heart. , 2000, Circulation research.

[23]  Jiahuai Han,et al.  PKC-dependent activation of p46/p54 JNKs during ischemic preconditioning in conscious rabbits. , 1999, American journal of physiology. Heart and circulatory physiology.

[24]  T. Tan,et al.  Inhibition of the c-Jun N-terminal kinase (JNK) signaling pathway by curcumin , 1998, Oncogene.

[25]  A. Clerk,et al.  The p38‐MAPK inhibitor, SB203580, inhibits cardiac stress‐activated protein kinases/c‐Jun N‐terminal kinases (SAPKs/JNKs) , 1998, FEBS letters.

[26]  Shokei Kim,et al.  Activation of mitogen-activated protein kinases and activator protein-1 in myocardial infarction in rats. , 1998, Cardiovascular research.

[27]  Y. Yazaki,et al.  Hypoxia and hypoxia/reoxygenation activate p65PAK, p38 mitogen-activated protein kinase (MAPK), and stress-activated protein kinase (SAPK) in cultured rat cardiac myocytes. , 1997, Biochemical and biophysical research communications.

[28]  Tsonwin Hai,et al.  Tissue-specific Pattern of Stress Kinase Activation in Ischemic/Reperfused Heart and Kidney* , 1997, The Journal of Biological Chemistry.

[29]  K. Yoshioka,et al.  A Novel Mechanism of JNK1 Activation , 1997, The Journal of Biological Chemistry.

[30]  K. Webster,et al.  Hypoxia/reoxygenation stimulates Jun kinase activity through redox signaling in cardiac myocytes. , 1997, Circulation research.

[31]  D. Buxton,et al.  Stimulation of c-Jun kinase and mitogen-activated protein kinase by ischemia and reperfusion in the perfused rat heart. , 1996, Biochemical and biophysical research communications.

[32]  M. Cohen,et al.  Preconditioning During Ischemia: Basic Mechanisms and Potential Clinical Applications , 1995 .