Nitric Oxide: an Anti‐fibrotic Factor in the Infarcted Myocardium?

In the infarcted myocardium, nitric oxide (NO) production is significantly increased, which is primarily derived from inducible NO synthase (iNOS) released by macrophages. However, its role on cardiac repair/remodeling is not completely defined. NO plays an antifibrotic role in various tissues including liver and skin. Herein, we tested our hypothesis that NO serves as a negative regulator on cardiac fibrosis in the infarcted myocardium. Wild‐type C57BL/6J mice and iNOS knockout mice were subjected to myocardial infarction by ligation of the left coronary artery. We studied the potential role of NO on collagen‐producing cell growth, profibrotic cytokine expression, collagen synthesis and degradation. In the infarcted myocardium at week 1, 2, 3 and 4 postMI. In the infarcted myocardium of wild‐type mice, we found: 1) myoFb appeared at wk 1, rapidly replicated and became abundant for over the course of 4 wks; 2) TGF‐b1 and type I collagen mRNA levels were significantly increased at wk1 and gradually declined thereafter although levels remained significantly higher than those in sham operated rats; 3) TIMP‐1 mRNA was significantly increased, while MMP‐1 mRNA levels remained low at all time points; and 4) collagen volume continuously increased for over the course of 4 wks. Thus, collagen synthesis is upregulated, while collagen degradation is suppressed in the infarcted myocardium, which leads to cardiac fibrosis. In iNOS−/− mice, myoFb proliferation and population, profibrotic cytokine expression, collagen synthesis and degradation as well as cardiac fibrosis were not significantly different compared to wild type mice. The present study suggests that NO does not serve as a negative regulator on fibrous tissue formation in the infarcted myocardium.