A8374 Kruppel like factor 15 attenuates activation of adventitial fibroblasts-mediated angiotensin II-induced vascular remodeling

Abstract

Objectives: Vascular remodeling is characterized by hypertrophy, vascular fibrosis and inflammation, but the precise mechanism underlying adventitial fibroblast-mediated vascular remodeling is not fully understood. We aim to determine whether transcription factor KLF15 (Krüppel-like factor 15) negatively regulate adventitial fibroblast activation contributing to vascular fibrosis and inflammation after Ang II (Angiotensin II) infusion. Methods: Male 8-week-old C57BL/6 mice were randomly divided into AdCTL group, Ang II + AdCTL group, Ang II + AdKLF15 group, Ang II + AdKLF15-ΔTAD (deletion of transactivation domain) group and Ang II + Losartan potassium group. Vascular morphology changes, adventitial fibrosis and inflammation, and KLF15 expression were detected. Primary culture of adventitial fibroblasts were used for cell function and mechanism study. Results: KLF15 was mainly expressed in vascular adventitia and intima. Ang II infusion-induced decrease of KLF15 expression especially in adventitia. Adenovirus-mediated overexpression of AdKLF15, but not AdKLF15-ΔTAD, attenuated vascular fibrosis, inflammation and TGF-beta signaling activation. Similarly, administered with Losartan potassium restored the expression of KLF15 and ameliorated Ang II-induced vascular remodeling. In adventitial fibroblasts, Ang II induced decrease of KLF15 in a dose- and time-dependent manner. Moreover, Ang II induced inflammation and fibrosis response, as well as the enhanced proliferation and migration of adventitial fibroblasts was suppressed by overexpression of KLF15 but not KLF15-ΔTAD. Conversely, these effects were aggravated by siRNA knockdown of KLF15. Conclusion: KLF15-dependent adventitial fibroblasts activation plays an important role in Ang II-induced vascular remodeling, likely through transactivation domain of KLF15.