Myocardial ischemia-reperfusion injury is exacerbated in absence of endothelial cell nitric oxide synthase.

Myocardial ischemia and reperfusion (MI/R) initiates a cascade of polymorphonuclear neutrophil (PMN)-mediated injury, the magnitude of which may be influenced by the bioavailability of nitric oxide (NO). We investigated the role of endothelial cell nitric oxide synthase (ecNOS) in MI/R injury by subjecting wild-type and ecNOS-deficient (-/-) mice to 20 min of coronary artery occlusion and 120 min of reperfusion. Myocardial infarct size represented 20.9 +/- 2.9% of the ischemic zone in wild-type mice, whereas the ecNOS -/- mice had significantly (P < 0.01) larger infarcts measuring 46.0 +/- 3.8% of the ischemic zone. Because P-selectin is thought to be involved with the pathogenesis of neutrophil-mediated I/R injury, we assessed the effects of MI/R on P-selectin expression in the myocardium of wild-type and ecNOS -/- mice. P-selectin expression measured with a radiolabeled monoclonal antibody (MAb) technique after MI/R in wild-type mice was 0.037 +/- 0.009 microgram MAb/g tissue, whereas ecNOS -/- coronary vasculature was characterized by significantly (P < 0.05) higher P-selectin expression (0.080 +/- 0.013 microgram MAb/g tissue). Histological examination of the postischemic myocardium revealed significantly (P < 0.01) more neutrophils in the ecNOS -/- (29.5 +/- 2.5 PMN/field) compared with wild-type (5.0 +/- 0.9 PMN/field) mice. A similar trend in infarct size and neutrophil accumulation was observed when wild-type and ecNOS -/- mice were subjected to 30 min of ischemia and 120 min of reperfusion. These novel in vivo findings demonstrate a cardioprotective role for ecNOS-derived NO in the ischemic-reperfused mouse heart.

[1]  P. Kubes,et al.  Inhaled NO as a viable antiadhesive therapy for ischemia/reperfusion injury of distal microvascular beds. , 1998, The Journal of clinical investigation.

[2]  O. Feron,et al.  Nitric oxide synthases: which, where, how, and why? , 1997, Journal of Clinical Investigation.

[3]  D. Anderson,et al.  Endothelial cell adhesion molecule expression in gene-targeted mice. , 1997, American Journal of Physiology.

[4]  P. Huang,et al.  Pulmonary vasoconstriction and hypertension in mice with targeted disruption of the endothelial nitric oxide synthase (NOS 3) gene. , 1997, Circulation research.

[5]  G. Zimmerman,et al.  Leukocyte activation induces surface redistribution of P‐selectin glycoprotein ligand‐1 , 1997, Journal of leukocyte biology.

[6]  P. Marsden,et al.  Cloning and characterization of murine endothelial constitutive nitric oxide synthase. , 1996, Biochimica et biophysica acta.

[7]  P. Libby,et al.  Nitric Oxide Attenuates Vascular Smooth Muscle Cell Activation by Interferon- , 1996, The Journal of Biological Chemistry.

[8]  M. Entman,et al.  Myocardial ischemia and reperfusion: a murine model. , 1995, The American journal of physiology.

[9]  M. Curtis,et al.  Effects of NO modulation on cardiac arrhythmias in the rat isolated heart. , 1995, Circulation research.

[10]  K. Okumura,et al.  Soluble P-selectin is released into the coronary circulation after coronary spasm. , 1995, Circulation.

[11]  N. Maulik,et al.  Nitric oxide signaling in ischemic heart. , 1995, Cardiovascular research.

[12]  T. Ueno,et al.  Increased soluble form of P-selectin in patients with unstable angina. , 1995, Circulation.

[13]  M. Moskowitz,et al.  Hypertension in mice lacking the gene for endothelial nitric oxide synthase , 1995, Nature.

[14]  J. Loscalzo,et al.  Nitric oxide and its role in the cardiovascular system. , 1995, Progress in cardiovascular diseases.

[15]  A. Buda,et al.  Intracoronary nitric oxide improves postischemic coronary blood flow and myocardial contractile function. , 1995, The American journal of physiology.

[16]  R. Schulz,et al.  Inhibition of nitric oxide synthesis protects the isolated working rabbit heart from ischaemia-reperfusion injury. , 1995, Cardiovascular research.

[17]  P. Libby,et al.  Nitric oxide decreases cytokine-induced endothelial activation. Nitric oxide selectively reduces endothelial expression of adhesion molecules and proinflammatory cytokines. , 1995, The Journal of clinical investigation.

[18]  P. Libby,et al.  Induction and Stabilization of IκBα by Nitric Oxide Mediates Inhibition of NF-κB (*) , 1995, The Journal of Biological Chemistry.

[19]  D. Yellon,et al.  Inhibition of nitric oxide synthesis reduces infarct size by an adenosine-dependent mechanism. , 1995, Circulation.

[20]  A. Buda,et al.  A novel sialyl LewisX analog attenuates neutrophil accumulation and myocardial necrosis after ischemia and reperfusion. , 1994, Circulation.

[21]  A. M. Lefer,et al.  Nitric oxide attenuates leukocyte-endothelial interaction via P-selectin in splanchnic ischemia-reperfusion. , 1994, The American journal of physiology.

[22]  A. M. Lefer,et al.  Inhibition of endothelial-derived nitric oxide promotes P-selectin expression and actions in the rat microcirculation. , 1994, Gastroenterology.

[23]  A. M. Lefer,et al.  Sialyl Lewisx-containing oligosaccharide attenuates myocardial reperfusion injury in cats. , 1994, The Journal of clinical investigation.

[24]  S. Vatner,et al.  Inhibition of Endothelium‐Derived Relaxing Factor Enhances Myocardial Stunning in Conscious Dogs , 1993, Circulation.

[25]  D. Lefer,et al.  Antineutrophil and Myocardial Protecting Actions of a Novel Nitric Oxide Donor After Acute Myocardial Ischemia and Reperfusion in Dogs , 1993, Circulation.

[26]  P. Kubes,et al.  Nitric oxide prevents leukocyte adherence: role of superoxide. , 1993, The American journal of physiology.

[27]  M. Topham,et al.  Inflammatory roles of P-selectin. , 1993, The Journal of clinical investigation.

[28]  D. Yellon,et al.  Inhibition of nitric oxide limits infarct size in the in situ rabbit heart. , 1993, Biochemical and biophysical research communications.

[29]  A. M. Lefer,et al.  In vivo neutralization of P-selectin protects feline heart and endothelium in myocardial ischemia and reperfusion injury. , 1993, The Journal of clinical investigation.

[30]  M. Lewis,et al.  SIN‐1 Reduces Platelet Adhesion and Platelet Thrombus Formation in a Porcine Model of Balloon Angioplast , 1993, Circulation.

[31]  L. Lasky,et al.  Selectins: interpreters of cell-specific carbohydrate information during inflammation. , 1992, Science.

[32]  A. M. Lefer,et al.  The Role of L‐Arginine in Ameliorating Reperfusion Injury After Myocardial Ischemia in the Cat , 1992, Circulation.

[33]  P. Kubes,et al.  Nitric oxide modulates microvascular permeability. , 1992, The American journal of physiology.

[34]  A. A. Taylor,et al.  Inflammation in the course of early myocardial ischemia , 1991, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[35]  P. Kubes,et al.  Nitric oxide: an endogenous modulator of leukocyte adhesion. , 1991, Proceedings of the National Academy of Sciences of the United States of America.

[36]  A. M. Lefer,et al.  Cardioprotective effects of authentic nitric oxide in myocardial ischemia with reperfusion , 1991, Critical care medicine.

[37]  A. Hassid,et al.  Nitric oxide-generating vasodilators and 8-bromo-cyclic guanosine monophosphate inhibit mitogenesis and proliferation of cultured rat vascular smooth muscle cells. , 1989, The Journal of clinical investigation.

[38]  S. Moncada,et al.  The anti‐aggregating properties of vascular endothelium: interactions between prostacyclin and nitric oxide , 1987, British journal of pharmacology.

[39]  P. Chomczyński,et al.  Single-step method of RNA isolation by acid guanidinium thiocyanate-phenol-chloroform extraction. , 1987, Analytical biochemistry.

[40]  T. Kao,et al.  Isolation and characterization of rat and human glyceraldehyde-3-phosphate dehydrogenase cDNAs: genomic complexity and molecular evolution of the gene. , 1985, Nucleic acids research.

[41]  R. Furchgott,et al.  The obligatory role of endothelial cells in the relaxation of arterial smooth muscle by acetylcholine , 1980, Nature.

[42]  A. Buda,et al.  Effects of a monoclonal antibody directed against P-selectin after myocardial ischemia and reperfusion. , 1996, The American journal of physiology.

[43]  A. Buda,et al.  Nitric oxide attenuates neutrophil-mediated myocardial contractile dysfunction after ischemia and reperfusion. , 1996, Circulation research.

[44]  T. Aw,et al.  Microvascular responses to inhibition of nitric oxide production. Role of active oxidants. , 1995, Circulation research.

[45]  P. Libby,et al.  Induction and stabilization of I kappa B alpha by nitric oxide mediates inhibition of NF-kappa B. , 1995, The Journal of biological chemistry.

[46]  中西 克彦.  Intracoronary L-arginine during reperfusion improves endothelial function and reduces infarct size , 1994 .

[47]  C. Wainwright,et al.  Pirsidomine, A Novel Nitric Oxide Donor, Suppresses Ischemic Arrhythmias in Anesthetized Pigs , 1993, Journal of Cardiovascular Pharmacology.

[48]  B. Lucchesi,et al.  Modulation of leukocyte-mediated myocardial reperfusion injury. , 1990, Annual review of physiology.

[49]  K. Peuhkurinen.  [Myocardial reperfusion--a double-edged sword?]. , 1989, Duodecim; laaketieteellinen aikakauskirja.