Abstract 17501: Cardiomyocyte Regulates Cardiac Fibrosis through Cell to Cell Interaction Mediated by KLF6
Introduction: Previous studies suggest that Krüppel-like factors (KLFs) play important roles in the cardiovasculature. We had previously identified and cloned KLF6, whose homozygous mutation in mice results in embryonic lethality with markedly reduced yolk sac vascularization suggesting a role in cardiovascular development. Preliminary investigation has shown significantly diminished levels of cardiac fibrosis in response to continuous angiotensin II (AngII) infusion (fibrotic area; wild-type mice: klf6+/- mice = 5.24%:1.6%) and remarkably reduced infiltration of macrophages in klf6+/- mice with induction of KLF6 in the nucleus of cardiomyocytes. However, it had yet to be addressed the precise mechanism how KLF6 contributes to cardiac remodeling.
Results: To clarify the inflammatory initiation of cardiac fibrosis, we carried out bone marrow transplantation from GFP mouse to klf6+/- mouse and flow cytometric analysis of cardiac infiltrating cells, which revealed marked difference in polarization of macrophages (M1: M2 = wild-type mice, 21: 64%, klf6+/- mice, 44: 42%). Co-culture analysis showed the importance of directional signals from stimulated cardiomyoctes to macrophages in regulation of recruitment and polarity change. Further investigation using cardiac specific KLF6 deletion mouse also showed significantly decreased cardiac fibrosis, reinforcing the importance of cardiomyocyte specific KLF6 expression. Mechanistically, we confirmed increased activation of IL-6/gp130 signaling in the early phase and altered expression levels of thrombospondins in the subacute phase of the stimulated klf6+/- mouse heart.
Conclusion: These molecules subsequently recruit monocytes, modulate their polarization and shift activation state of residual cardiac fibroblasts or transform them into myofibroblasts in the early stage of Ang II induced cardiac fibrosis. This would be a new regulation pathway of cardiac remodeling that KLF6 induced in the stimulated cardiomyocyte regulates expression levels of cytokines or other modulating factors thus mediating cell to cell interaction in cardiac fibrosis.
- © 2012 by American Heart Association, Inc.