Abstract 8655: Caveolin-1-dependent Inhibition of Transforming Growth Factor-β Pathway Alters Inflammation Post Myocardial Infarction
Myocardial Infarction (MI) leads to inflammatory events characterized by influx of neutrophils and macrophages, altering the local cytokine milieu. TGF-β is implicated as one of the key cytokines in this process. Caveolin-1 (Cav-1), the main structural protein of caveolae, negatively modulates TGF-β signaling by regulating TGF-β receptor turnover and downstream signaling. Thus, we hypothesized that Cav-1 will modulate TGF-β anti-inflammatory responses post-MI. Two-month old wild-type (WT) C57BL/6 and the Cav-1 null mice were subjected to left anterior descending artery ligation, a subset of which were treated with TGF-β neutralizing antibodies, 24 hours post-MI. Hearts were harvested 3 days post-injury. H & E staining showed massive cell infiltration in WT mice post-MI in all groups. Neutrophil and macrophage counts paralleled this observation. Interestingly, in the Cav-1 null mice, a marked reduction in the infiltrating neutrophil and macrophage numbers was observed after anti-TGF-β treatment. Real-time PCR results further confirmed the regulatory effects of Cav-1 in the inflammatory responses. Thirty-five percent of the regulated inflammatory genes were TGF-β dependent (such as chemokine genes Ccl24 and Ccr9; cytokine genes IL-17b and Spp1 and cytokine receptor gene IL1r2). Out of them, 60% were Cav-1-dependent. For example, Ccl24, Ccr9 and IL1r2 were Cav-1 dependent whereas Spp-1 was regulated independently of Cav-1. Ccl24 expression was increased 20-fold in Cav-1 null mice post-MI compared to WT mice. This increase was further enhanced after anti-TGF-β antibody treatment. Similar results were obtained for Ccr9 and IL1r2 expressions. Spp-1 expression was upregulated by 600-fold post-MI in WT and by 400-fold in Cav-1 null mice. After anti-TGF-β antibody treatment, Spp-1 expression returned to baseline in both strains. Thus, we demonstrate for the first time that in addition to TGF-β, Cav-1 plays a significant role in the inflammatory events post-MI; and regulating TGF-β and/or Cav-1 modulates these events. It would be interesting to study if Cav-1 has a role to play in the chemotaxis of the immune cells to the site of injury and in conjunction with TGF-β, affect the secretion of cytokines and chemokines by these cells, altering post-MI events.
- © 2011 by American Heart Association, Inc.