title: Circulating NOS3 modulates left ventricular remodeling following reperfused myocardial infarction.
abstract: OBJECTIVE
  Nitric oxide (NO) is constitutively produced and released from the endothelium and several blood cell types by the isoform 3 of the NO synthase (NOS3). We have shown that NO protects against myocardial ischemia/reperfusion (I/R) injury and that depletion of circulating NOS3 increases within 24 h of ischemia/reperfusion the size of myocardial infarction (MI) in chimeric mice devoid of circulating NOS3. In the current study we hypothesized that circulating NOS3 also affects remodeling of the left ventricle following reperfused MI.
  
  
  METHODS
  To analyze the role of circulating NOS3 we transplanted bone marrow of NOS3-/- and wild type (WT) mice into WT mice, producing chimerae expressing NOS3 only in vascular endothelium (BC-/EC+) or in both, blood cells and vascular endothelium (BC+/EC+). Both groups underwent 60 min of coronary occlusion in a closed-chest model of reperfused MI. During the 3 weeks post MI, structural and functional LV remodeling was serially assessed (24 h, 4 d, 1 w, 2 w and 3 w) by echocardiography. At 72 hours post MI, gene expression of several extracellular matrix (ECM) modifying molecules was determined by quantitative RT-PCR analysis. At 3 weeks post MI, hemodynamics were obtained by pressure catheter, scar size and collagen content were quantified post mortem by Gomori's One-step trichrome staining.
  
  
  RESULTS
  Three weeks post MI, LV end-systolic (53.2±5.9 μl; ***p≤0.001; n = 5) and end-diastolic volumes (82.7±5.6 μl; *p<0.05; n = 5) were significantly increased in BC-/EC+, along with decreased LV developed pressure (67.5±1.8 mm Hg; n = 18; ***p≤0.001) and increased scar size/left ventricle (19.5±1.5%; n = 13; **p≤0.01) compared to BC+/EC+ (ESV: 35.6±2.2 μl; EDV: 69.1±2.6 μl n = 8; LVDP: 83.2±3.2 mm Hg; n = 24; scar size/LV13.8±0.7%; n = 16). Myocardial scar of BC-/EC+ was characterized by increased total collagen content (20.2±0.8%; n = 13; ***p≤0.001) compared to BC+/EC+ (15.9±0.5; n = 16), and increased collagen type I and III subtypes.
  
  
  CONCLUSIONS
  Circulating NOS3 ameliorates maladaptive left ventricular remodeling following reperfused myocardial infarction.
authors: Medical Faculty, Division of Cardiology, Pulmonology & Vascular Medicine, Heinrich-Heine-University, Düsseldorf, Germany.
authors: Simone
authors: S
authors: Gorressen
authors: Medical Faculty, Division of Cardiology, Pulmonology & Vascular Medicine, Heinrich-Heine-University, Düsseldorf, Germany.
authors: Manuel
authors: M
authors: Stern
authors: Medical Faculty, Division of Cardiology, Pulmonology & Vascular Medicine, Heinrich-Heine-University, Düsseldorf, Germany.
authors: Annette M
authors: AM
authors: van de Sandt
authors: Medical Faculty, Division of Cardiology, Pulmonology & Vascular Medicine, Heinrich-Heine-University, Düsseldorf, Germany.
authors: Miriam M
authors: MM
authors: Cortese-Krott
authors: Medical Faculty, Division of Cardiology, Pulmonology & Vascular Medicine, Heinrich-Heine-University, Düsseldorf, Germany.
authors: Jan
authors: J
authors: Ohlig
authors: Medical Faculty, Division of Cardiology, Pulmonology & Vascular Medicine, Heinrich-Heine-University, Düsseldorf, Germany.
authors: Tienush
authors: T
authors: Rassaf
authors: Medical Faculty, Department of Cardiovascular Physiology, Heinrich-Heine-University, Düsseldorf, Germany; CARID, Cardiovascular Research Institute Düsseldorf, Düsseldorf, Germany.
authors: Axel
authors: A
authors: Gödecke
authors: CARID, Cardiovascular Research Institute Düsseldorf, Düsseldorf, Germany; Medical Faculty, Institute of Pharmacology und Clinical Pharmacology, Heinrich Heine University, Cardiovascular Research Institute Düsseldorf (CARID), Düsseldorf, Germany.
authors: Jens W
authors: JW
authors: Fischer
authors: Institute for Pathophysiology, West German Heart and Vascular Center Essen, University of Essen Medical School, Essen, Germany.
authors: Gerd
authors: G
authors: Heusch
authors: Medical Faculty, Division of Cardiology, Pulmonology & Vascular Medicine, Heinrich-Heine-University, Düsseldorf, Germany; Department of Cardiology, Vascular Medicine and Intensive Care Medicine, Robert Koch Krankenhaus, Klinikum Region Hannover, Hannover, Germany.
authors: Marc W
authors: MW
authors: Merx
authors: Medical Faculty, Division of Cardiology, Pulmonology & Vascular Medicine, Heinrich-Heine-University, Düsseldorf, Germany; CARID, Cardiovascular Research Institute Düsseldorf, Düsseldorf, Germany.
authors: Malte
authors: M
authors: Kelm
mesh_terms: D000818:Animals; D002921:Cicatrix / Q000378:metabolism / Q000473:pathology; D003094:Collagen / Q000032:analysis; D005355:Fibrosis; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009203:Myocardial Infarction / Q000201:enzymology* / Q000473:pathology; D015428:Myocardial Reperfusion Injury / Q000201:enzymology* / Q000473:pathology; D009569:Nitric Oxide / Q000502:physiology; D052250:Nitric Oxide Synthase Type III / Q000097:blood / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D011828:Radiation Chimera; D013318:Stroke Volume; D018487:Ventricular Dysfunction, Left / Q000201:enzymology / Q000209:etiology / Q000503:physiopathology; D020257:Ventricular Remodeling / Q000502:physiology*
chemical_list: D009569:Nitric Oxide; D003094:Collagen; D052250:Nitric Oxide Synthase Type III; C496315:Nos3 protein, mouse