title: Depletion of circulating blood NOS3 increases severity of myocardial infarction and left ventricular dysfunction.
abstract: Nitric oxide (NO) derived from endothelial NO synthase (NOS3) plays a central role in myocardial ischemia/reperfusion (I/R)-injury. Subsets of circulating blood cells, including red blood cells (RBCs), carry a NOS3 and contribute to blood pressure regulation and RBC nitrite/nitrate formation. We hypothesized that the circulating blood born NOS3 also modulates the severity of myocardial infarction in disease models. We cross-transplanted bone marrow in wild-type and NOS3(-/-) mice with wild-type mice, producing chimeras expressing NOS3 only in vascular endothelium (BC-/EC+) or in both blood cells and vascular endothelium (BC+/EC+). After 60-min closed-chest coronary occlusion followed by 24 h reperfusion, cardiac function, infarct size (IS), NOx levels, RBCs NO formation, RBC deformability, and vascular reactivity were assessed. At baseline, BC-/EC+ chimera had lower nitrite levels in blood plasma (BC-/EC+: 2.13 ± 0.27 μM vs. BC+/EC+ 3.17 ± 0.29 μM; *p < 0.05), reduced DAF FM associated fluorescence within RBCs (BC-/EC+: 538.4 ± 12.8 mean fluorescence intensity (MFI) vs. BC+/EC+: 619.6 ± 6.9 MFI; ***p < 0.001) and impaired erythrocyte deformability (BC-/EC+: 0.33 ± 0.01 elongation index (EI) vs. BC+/EC+: 0.36 ± 0.06 EI; *p < 0.05), while vascular reactivity remained unaffected. Area at risk did not differ, but infarct size was higher in BC-/EC+ (BC-/EC+: 26 ± 3 %; BC+/EC+: 14 ± 2 %; **p < 0.01), resulting in decreased ejection fraction (BC-/EC+ 46 ± 2 % vs. BC+/EC+: 52 ± 2 %; *p < 0.05) and increased end-systolic volume. Application of the NOS inhibitor S-ethylisothiourea hydrobromide was associated with larger infarct size in BC+/EC+, whereas infarct size in BC-/EC+ mice remained unaffected. Reduced infarct size, preserved cardiac function, NO levels in RBC and RBC deformability suggest a modulating role of circulating NOS3 in an acute model of myocardial I/R in chimeric mice.
authors.affiliation: Division of Cardiology, Pneumology and Angiology, Department of Medicine, University Hospital Düsseldorf, Moorenstrasse 5, 40225, Düsseldorf, Germany, marc.merx@med.uni-duesseldorf.de.
authors.forename: Marc W
authors.initials: MW
authors.lastname: Merx
authors.forename: Simone
authors.initials: S
authors.lastname: Gorressen
authors.forename: Annette M
authors.initials: AM
authors.lastname: van de Sandt
authors.forename: Miriam M
authors.initials: MM
authors.lastname: Cortese-Krott
authors.forename: Jan
authors.initials: J
authors.lastname: Ohlig
authors.forename: Manuel
authors.initials: M
authors.lastname: Stern
authors.forename: Tienush
authors.initials: T
authors.lastname: Rassaf
authors.forename: Axel
authors.initials: A
authors.lastname: Gödecke
authors.forename: Mark T
authors.initials: MT
authors.lastname: Gladwin
authors.forename: Malte
authors.initials: M
authors.lastname: Kelm
mesh_terms: D000818:Animals; D015153:Blotting, Western; D004195:Disease Models, Animal; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009203:Myocardial Infarction / Q000097:blood* / Q000473:pathology / Q000503:physiopathology; D015428:Myocardial Reperfusion Injury / Q000097:blood / Q000473:pathology / Q000503:physiopathology; D009569:Nitric Oxide / Q000097:blood; D052250:Nitric Oxide Synthase Type III / Q000097:blood*; D018183:Transplantation Chimera; D018487:Ventricular Dysfunction, Left / Q000097:blood* / Q000473:pathology / Q000503:physiopathology
chemical_list: D009569:Nitric Oxide; D052250:Nitric Oxide Synthase Type III