Abstract 11185: Hypoxic Responses of M1 Macrophages are Critical for the Regulation of Cardiac Fibrosis
Hypoxia is a pathological condition in which the tissue is deprived of adequate oxygen supply. It occurs in myocardial ischemia and cardiac hypertrophy, and accelerates the inflammatory processes in cardiac tissue. While each cell exerts its own responses to hypoxia, most of them are mainly mediated through the transcription factor, hypoxia inducible factor- 1α (HIF- 1α). Macrophages are key mediators of inflammation, and are activated in hypoxic areas, and can be classified as M1 (pro-inflammatory) and M2 (anti-inflammatory) type. However, the precise roles of macrophages in cardiac hypertrophy or fibrosis are still unclear. To analyze the roles of macrophage hypoxia signaling in cardiac remodeling, we performed transverse aortic constriction (TAC), a well-established experimental model for pressure overload-induced cardiac hypertrophy and fibrosis in mice. Using flow cytometric (FACS) analysis, we characterized the inflammatory cells that were recruited to the heart after TAC. We found that at 2 and 4 days after TAC, CD11b positive F4/80 mid macrophages accumulated in the heart. Using pimonidazole, a probe for hypoxia, we then analyzed for those cells that may have been distributed in hypoxic areas, and identified that M1 macrophages (CD11b positive, F4/80 mid, Ly6G negative, Ly6c positive) markedly accumulated in these areas. We previously demonstrated that HIF- 1α plays a critical role in M1 macrophage activation. To verify the roles of hypoxia mediated activation of M1 macrophages in cardiac remodeling, we generated myeloid specific HIF-1α knockout mice (mHIF-1α KO) and examined the effect of TAC-induced cardiac remodeling in these mice. While there were no significant differences in the degree of cardiac hypertrophy between mHIF-1α KO and wild type mice, myocardial fibrosis was more pronounced in mHIF-1α KO mice. The number of α-SMA-positive cells, a marker of myofibroblasts, was also significantly elevated in mHIF-1α KO mice, suggesting the activation of myofibroblasts. These results demonstrate the importance of M1 macrophage hypoxic response in the regulation of cardiac fibrosis, as well as suggesting macrophages may have novel interactions with cardiac fibroblasts during cardiac remodeling.
- © 2012 by American Heart Association, Inc.