Abstract 3339: Mindin, a Regulator of Innate Immunity and Inhibitor of Angiogenesis, Contributes to Mortality and Adverse Remodeling Post Myocardial Infarction
Mindin (Spondin 2) is a highly conserved secreted extracellular matrix (ECM) protein of the Mindin-F-spondin family. Previous studies showed Mindin to be a regulator of host innate immunity, but despite its high expression in the heart, its role in cardiac stress response is unknown. The objective of this study was to determine the role of Mindin following myocardial infarction (MI) with loss-of-function Mindin−/− model. C57/BL wild-type (WT) mice or Mindin−/− mice were randomized to permanent left anterior descending coronary artery ligation (LAD) or sham operation. Cardiac samples were collected on days 0, 3, 7, and 28 post MI. The animals were serially followed for mortality, gene expression and physiological endpoints. Following MI, the mortality of the Mindin−/− mice was significantly lower than that of WT mice (17.5% vs. 65.2%, p<0.0001). This was accompanied by a significant reduction in rupture in Mindin−/− mice (14.4% vs. 62.3%). In the WT mice, Mindin expression levels increased further on day 7 post MI, but returned back to baseline level by day 28. Mindin−/− mice on the other hand showed significantly reduced infarct size and heart-weight/body-weight ratio compared to WT mice. Consistent with Mindin’s ECM localization, cardiac matrix metalloproteinase (MMP)-9 and -2 activities in the infarcted myocardium were significantly decreased in Mindin−/− mice than in WT mice. As an innate immune regulator, Mindin−/− mice showed reduced NF-kB activation and macrophage recruitment, and these were accompanied by a decrease in pro-apoptotic proteins (caspase 3, 8 and 9, Bad, Bax, and Bik) and an increase in pro-survival protein of MAPK (p44/42) in Mindin−/− mice. Mindin is a putative inhibitor of angiogenesis, and Mindin−/− mice did show an increase in angiogenic factors such as vascular endothelial growth factor (VEGF) post MI. We conclude that Mindin is a significant contributor to mortality and acute adverse remodeling post infarction. This is partly through its unique attributes of innate immune regulator and inhibitor of angiogenesis. Mindin may be an interesting biomarker or therapeutic target post MI.