Abstract 17973: KLF6 Modulates Aortic Aneurysm Formation by Balancing Between Inflammatory and TGFβ Signaling Pathways
[Background] The transcription factor, Krüppel-like factor 6 (KLF6) has been shown to play important roles in the regulation of diverse cellular processes through TGFβ signaling. Recently, TGFβ signaling has been reported to be a central mechanism of aortic remodeling, such as Marfan syndrome. We reasoned that exploring the role of KLF6 in aortic remodeling, namely abdominal aortic aneurysm (AAA) formation, would better clarify involved pathogenic mechanism.
[Methods and Results] CaCl2 stimulation to abdominal aorta followed by angiotensin II (AngII, 1500 ng/kg/min) infusion for 2 weeks was done to obtain aortic aneurysm formation. klf6+/- mice showed destruction of the aortic wall structure and increased accumulation of extracellular matrix surrounding the aorta. klf6+/- mice exhibited significantly increased expression levels of IL-6 and factors of the IL-6-dependent pathway including STAT3, SOCS3 and iNOS, while expression levels of TGFβ1 and thrombospondin-1 were decreased. This inverse regulation between IL-6 and TGFβ1 signaling was also observed in macrophage derived from bone marrow of klf6+/-mice with LPS stimulation. Further, mice with macrophage-specific KLF6 deletion showed accelerated aortic remodeling, confirming the importance of macrophage regulation by KLF6 in the development of aortic aneurysms.
[Conclusion] In our model, KLF6 exerts bimodal regulation through IL-6/STAT3 and TGFβ signaling in AAA formations, as a critical transcriptional regulator modulating aortic inflammatory and/or fibrotic responses. Understanding the regulatory pathway through KLF6 on AAA formation would provide new insight into the pathogenic mechanisms of AAA development.
- © 2012 by American Heart Association, Inc.