The massive loss of cardiomyocytes after myocardial infarction often results in cardiac fibrosis, chamber dilatation and heart failure. Several studies have shown that inflammation contributes to adverse left ventricular remodeling, however, anti-inflammatory therapy with NSAID during the acute phase of myocardial infarction augments the adverse cardiac remodeling and increases mortality. We hypothesized that inflammation in the acute phase of myocardial infarction might trigger the activation of cardiac progenitors and that anti-inflammatory therapy might attenuate the repair by the cardiac progenitors.
We confirmed that Nkx2.5 enhancer-expressing cells existed in the postnatal mouse heart and could differentiate into striated cardiomyocytes in vitro. Using the Nkx2.5 enhancer-eGFP transgenic mice, we found the number of eGFP+ cells and inflammatory cells (marked by Gr1. Mac1, B220, CD45) increased remarkably and significantly after coronary artery ligation. The activated Nkx2.5 enhancer expressing cells expressed up-regulated cardiogenesis genes and could differentiate into cardiomyocytes in vivo by lineage tracing.
To prove that anti-inflammatory therapy might attenuate the repair by the cardiac progenitors, we added NSAID (ibuprofen) to the feeding water after coronary ligation on the Nkx2.5-eGFP transgenic mice and found the activated level of progenitor cells was decreased by 73% after the mice were treated with ibuprofen. We further lineage-traced the post-inury inducible Nkx2.5-Cre; ROSA26-LacZ double transgenic mice with ibuprofen or water and found the LacZ+ positive area was decreased by 80% in the heart sections of ibuprofen-treated mice.
We concluded that the inflammatory signaling enhances the cardiac progenitor cells to proliferate and differentiate into cardiomyocytes. Understanding the factors regulating cardiac regeneration helps us treat the patients with myocardial infarction or heart failure.
