The role of the BMP antagonist Gremlin 2 during cardiac tissue repair

Abstract

CELL AND DEVELOPMENTAL BIOLOGY

The role of the BMP antagonist Gremlin2 during cardiac tissue repair

Lehanna Nalani Sanders

Dissertation under the direction of Professor Antonis Hatzopoulos Acute myocardial infarction (MI) or heart attack occurs when an artery becomes occluded, preventing blood flow thereby causing severe cardiac cell loss. Massive cell death induces an inflammatory response, which leads to granulation tissue deposition and eventual scar formation. This results in cardiac tissue remodeling and heart failure. Although these sequential events of cardiac tissue repair have been well described, the regulation of each phase is not entirely understood. Molecular pathways necessary for development are often re-activated during injury. The BMP pathway has been known to be important for cardiac development and morphogenesis as well as being induced post-MI. However it’s role in the tissue repair process or how it is regulated is not well known. We recently showed that the Bone Morphogenetic Protein (BMP) antagonist Gremlin 2 (Grem2) is required for cardiac tube looping and cardiomyocyte differentiation during zebrafish development. In this work we show that in adult mice, BMP signaling components including Grem2 is strongly and transiently induced after myocardial infarction (MI) within the peri-infarct area during the inflammatory phase of cardiac tissue repair. By engineering loss- (Grem2-/-) and gain- (TGGrem2) of-Grem2-function mice, we discovered that Grem2 controls the magnitude of the inflammatory response and limits infiltration of inflammatory cells in peri-infarct ventricular tissue, improving cardiac function. Excessive inflammation in Grem2-/- mice after MI was due to overactivation of canonical BMP signaling and suppressed by the BMP inhibitor DMH1. Furthermore, intra-peritoneal administration of Grem2 protein in wild-type mice was sufficient to reduce inflammation after MI. Cellular analyses showed BMP2 acts synergistically with TNFα to induce expression of pro-inflammatory proteins in endothelial cells, whereas Grem2 specifically inhibits the BMP2 effect. The role of Grem2 appears to be specific to the inflammatory phase since changes in Grem2 expression did not directly alter the phenotype of the granulation tissue deposition and fibrotic phases of recovery. Finally, high-throughput sequencing analysis is being implemented in order to determine any previously unknown targets and interactions of Grem2 for future analysis.