Inducible nitric oxide synthase and tumor necrosis factor in animal models of myocardial necrosis induced by coronary artery ligation or isoproterenol injection.
BACKGROUND
Increased expression of inducible nitric oxide synthase (iNOS) has been described in humans with cardiomyopathies. Most animal models of ischemia-induced heart failure use the surgical ligation of coronary arteries. However, studies of iNOS expression in these models may be confounded by a robust immune response because of the surgical procedure itself leading to iNOS expression in the heart, as well as in other tissues.


RESULTS
iNOS expression was studied in adult male rats injected subcutaneously with either 250 mg/kg of isoproterenol (ISO) or vehicle on 2 consecutive days. This approach induces diffuse myocardial necrosis and leads to the development of a dilated cardiomyopathy. Hearts from ISO-injected animals harvested at 6 weeks had evidence of apical and subendocardial scarring. These hearts showed a 9.6-fold (left ventricle [LV], P = .004) and an 11.9-fold (right ventricle, P = .002) increase in the expression of tumor necrosis factor (TNF), and a 6.8-fold increase (LV, P = .0183) in iNOS messenger RNA compared with vehicle-injected controls. iNOS protein also was detectable by immmunoprecipitation in left ventricular muscle from ISO-injected animals, as well as by immunohistochemical analysis.


CONCLUSIONS
Expression of TNF and iNOS in the heart is increased in an experimental model of dilated cardiomyopathy that minimizes the confounding effects of surgery, supporting a role for the activation of innate immunity signaling pathways in the pathogenesis of heart failure.
Grosjean
S A
SA
Cardiovascular Division, Brigham and Women's Hospital, Boston, Massachusetts 02115, USA.
Arstall
M A
MA
Mitchell
R N
RN
Klappacher
G W
GW
Kelly
R A
RA
Pfeffer
M A
MA
Pfeffer
J M
JM
D000818:Animals; D015415:Biomarkers; D015152:Blotting, Northern; D003331:Coronary Vessels / Q000601:surgery*; D004195:Disease Models, Animal; D006352:Heart Ventricles / Q000378:metabolism* / Q000473:pathology; D007279:Injections, Subcutaneous; D007545:Isoproterenol; D008026:Ligation; D008297:Male; D009203:Myocardial Infarction / Q000139:chemically induced / Q000378:metabolism* / Q000473:pathology; D019001:Nitric Oxide Synthase / Q000096:biosynthesis* / Q000235:genetics; D052247:Nitric Oxide Synthase Type II; D011233:Precipitin Tests; D012333:RNA, Messenger / Q000235:genetics; D051381:Rats; D017208:Rats, Wistar; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis* / Q000235:genetics
D015415:Biomarkers; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496318:Nos2 protein, rat; D007545:Isoproterenol