Cardiac fibrogenesis following infarction in mice with deletion of inducible nitric oxide synthase.
BACKGROUND
Studies have shown that the absence of inducible nitric oxide synthase (iNOS) improves cardiac function and survival after myocardial infarction (MI). The responsible mechanisms, however, remain uncertain. Cardiac iNOS is significantly increased after MI, which is colocalized with fibrous tissue formation. Herein, we tested our hypothesis that iNOS is involved in the development of cardiac fibrosis.


METHODS
Wild-type and iNOS-knockout mice were subjected to MI by left coronary artery ligation. At week 1, 2, 3, and 4 post-MI, we addressed cardiac expression of profibrogenic mediator, growth of collagen-producing cells, collagen synthesis, and degradation.


RESULTS
In the infarcted myocardium of wild-type and iNOS-knockout mice, transforming growth factor (TGF)-beta1 expression was significantly increased, particularly in the early stage; myofibroblasts appeared and became abundant for over 4 weeks; matrix metalloproteinase-1 expression was low, whereas tissue inhibitor of matrix metalloproteinase-1 was significantly elevated; type-I collagen mRNA was significantly increased and collagen was continuously accumulated. In the noninfarcted myocardium, TGF-beta1 and type-I collagen mRNA levels as well as collagen volume were also elevated, but less evident than infarcted myocardium. However, there was no significant difference in cardiac TGF-beta1 expression, myofibroblast population, collagen synthesis/degradation, and collagen volume between wild-type and iNOS-knockout mice with MI.


CONCLUSIONS
The current study suggests that iNOS-induced nitric oxide production may not mediate cardiac fibrosis after MI. Thus, other mechanisms are involved in nitrosative stress-induced cardiac dysfunction after MI.
Division of Cardiovascular Diseases, University of Tennessee, Health Science Center, Memphis, Tennessee 38163, USA.
Li
L
Lu
Sue Si
SS
Chen
Aviv
A
Hassid
Yao
Y
Sun
D000818:Animals; D024042:Collagen Type I / Q000235:genetics; D004195:Disease Models, Animal; D005355:Fibrosis; D017353:Gene Deletion; D015870:Gene Expression / Q000187:drug effects; D007150:Immunohistochemistry; D017403:In Situ Hybridization; D008297:Male; D020781:Matrix Metalloproteinase 1 / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009203:Myocardial Infarction / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D009206:Myocardium / Q000201:enzymology / Q000378:metabolism / Q000473:pathology*; D009569:Nitric Oxide / Q000096:biosynthesis / Q000502:physiology*; D052247:Nitric Oxide Synthase Type II / Q000235:genetics / Q000502:physiology*; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000235:genetics; D053773:Transforming Growth Factor beta1 / Q000235:genetics
D024042:Collagen Type I; D019715:Tissue Inhibitor of Metalloproteinase-1; D053773:Transforming Growth Factor beta1; D009569:Nitric Oxide; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse; D020781:Matrix Metalloproteinase 1