The Role of p38 MAPK Mediated Paracrine Signaling from Cardiomyocytes to Endothelial Cells in vitro and in vivo.

摘要

p38 MAPK is a stress-activated kinase that plays a vital role in a number of biological events. In cardiac biology, p38 MAPK has been shown to be activated during pathological events such as ischemia and heart failure. While widely studied, much remains to be known about the exact role this kinase plays in the heart. In particular, little is known about the role p38 MAPK plays in paracrine signaling in the heart. The heart is composed of multiple cell types, including myocytes, fibroblast, vascular cells and inflammatory cells. In order to ensure proper function of the organ, especial during pathological stress, these various cells must communicate with each other. This can occur by both mechanical and chemical signaling. Previously, cardiomyocyte-specific p38 MAPK signaling has been shown regulate inflammatory cytokines, thus contributing to myocyte-inflammatory cell cross talk. However, p38 MAPK's role in other forms of cross talk is not known. Cross talk between cardiomyoytes and vascular cells is known to occur in both directions to ensure adequate perfusion of the tissue. During periods of stress, the heart often experiences an increased growth of the vascular network to help meet increased oxygen demands. Recent studies have suggested that an inadequate angiogenic response during periods of stress can adversely affect the function of the myocardium. Little is known about what controls the paracrine signaling from myocytes to regulate this angiogenic response. We have hypothesized that, as a stress activated kinase, p38 MAPK signaling in cardiomyocytes contributes to myocyte-endothelial cell cross talk via induction of paracrine signaling. Our work shows for the first time that activation of p38 MAPK in myocytes promotes endothelial cell growth via VEGF secretion in vitro. Furthermore, we show that loss of myocyte-specific p38 MAPK signaling blunts the angiogenic response in vivo under periods of pathological stress.