Abstract 1487: Cardiac Fibrogenesis Following Infarction in Mice with Targeted Deletion of Inducible Nitric Oxide Synthase
Background: Following myocardial infarction (MI), cardiac inducible nitric oxide synthase (iNOS) is significantly increased, leading to elevation of local nitric oxide production. However, the role of nitric oxide in the infarcted heart is not fully understood. Herein, we sought to determine whether nitric oxide is involved in the development of cardiac fibrosis following MI.
Methods: The growth of myofibroblasts, the balance between collagen synthesis and degradation, and the expression of profibrotic cytokines, particularly TGF-β1, are the major determinants for cardiac fibrous tissue formation. By using a MI model created by coronary artery ligation in wild type and iNOS knockout mice, we studied potential regulation of nitric oxide on the molecular and cellular events related to cardiac fibrosis in the infarcted heart. At week 1, 2, 3 and 4 postMI, myofibroblasts were detected by immunohistochemistry; expression of TGF-β1, type 1 collagen, MMP-1 and TIMP-1 was examined by quantitative in situ hybridization; and cardiac fibrosis was detected by picrosirius red staining and quantitated using image analyzing system.
Results: In the infarcted myocardium of both wild type and iNOS knockout mice, TGF-β1 expression was significantly increased, particularly in the early stage; 2) myofibroblasts appeared and became abundant for over 4 weeks; 3) MMP-1 expression was low, while TIMP-1 was significantly elevated; and 4) type I collagen mRNA was significantly increased and collagen was continuously accumulated. In the noninfarcted myocardium, TGF-β1 and type I collagen mRNA levels as well as collagen volume were also elevated, but less evident than in the infarcted myocardium. However, we did not observe the significant difference in profibrotic cytokine expression, myofibroblast population, collagen synthesis and degradation as well as collagen volume in the infarcted heart between wild type and iNOS knockout mice.
Conclusion: The current study suggests that following acute MI, cardiac collagen synthesis is activated, while collagen degradation is suppressed, thereby leading to cardiac fibrosis. Enhanced cardiac nitric oxide, however, does not serve as a regulator in fibrous tissue formation following MI.