Abstract 16792: KLF6 Modulates Recruitment and Polarization of Inflammatory Cells Through Cardiomyocytes in Initiation of Cardiac Fibrosis
Introduction: Previous studies suggest that Kråppel-like factors (KLFs) play important roles in the cardiovasculature. We 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. However, it has yet to be addressed how KLF6 contributes to cardiovascular disease.
Methods & Results: Preliminary investigation showed significantly diminished levels of cardiac fibrosis in response to continuous angiotensin II (Ang II) infusion (fibrotic area; wild-type: klf6+/- mice=5.24%:1.6%) in Klf6+/- mice. Immunohistochemical analysis revealed remarkably reduced infiltration of Mac3 positive cells in klf6+/- mice as soon as 1 to 5 days after initiation of Ang II stimulation and induction of KLF6 in the nucleus of cardiomyocytes. We further investigated infiltrating cells by flow cytometric analysis which revealed marked difference in polarization of macrophages infiltrating cardiac tissue (M1: M2= wild-type mice, 21: 64%, klf6+/- mice, 44: 42%). Microarray analysis confirmed reduced expression levels of thrombospondins in the stimulated klf6+/- mouse heart (thrombospondin-1 38.9%, thrombospondin-4 27.7%). These biologically active substances subsequently recruited monocytes and modulated their polarization, which in turn shifted activation of residual cardiac fibroblasts or transformation into myofibroblasts thus participating in the early stage of Ang II induced cardiac fibrosis.
Conclusion: KLF6 plays a functional role in the initiation of cardiac fibrosis in response to pathological stimuli mainly through modulation of recruitment and polarization of infiltrating monocytic cells by biologically active molecules like thrombospondins.
- © 2011 by American Heart Association, Inc.