Transactivation domain of Krüppel-like factor 15 negatively regulates angiotensin II-induced adventitial inflammation and fibrosis.
Krüppel-like factor (KLF) 15 has emerged as a critical regulator of fibrosis in cardiovascular diseases. However, the precise role that KLF15 and its functional domain played in adventitial inflammation and fibrosis remains unclear. This study aims to investigate the role of the transactivation domain (TAD) of KLF15 in angiotensin II (Ang II)-induced adventitial pathologic changes. KLF15 expression was decreased in the vascular adventitia of Ang II-infused mice (1000 ng/kg/min, 14 d) and in adventitial fibroblasts (AFs) stimulated by Ang II (10-7 M). Adenovirus-mediated KLF15 overexpression normalized Ang II-induced vascular hypertrophy, increased collagen deposition, macrophage infiltration, and CCL2 and VCAM-1 expression. Interestingly, KLF15-ΔTAD (KLF15 with deletion of TAD at amino acids 132-152) overexpression showed no effect on the above pathologic changes. Similarly, perivascularly overexpression of KLF15 but not KLF15-ΔTAD in carotid arteries also attenuated Ang II-induced vascular inflammation and fibrosis. Furthermore, KLF15 overexpression after Ang II infusion rescued Ang II-induced vascular remodeling. CCL2 or VCAM-1-mediated monocyte and macrophage migration or adhesion to AFs in response to Ang II was negatively regulated by KLF15 through TAD. Ang II-enhanced Smad2/3 activation and adventitial migration, proliferation, and differentiation of AFs were suppressed by KLF15 but not KLF15-ΔTAD overexpression. Conversely, small interfering RNA knockdown of KLF15 aggravated Ang II-induced Smad2/3 activation and dysfunction of AFs. Luciferase, coimmunoprecipitation, and chromatin immunoprecipitation assay were used to demonstrate that interaction of KLF15 with Smad2/3 suppressed CCL2 expression through TAD. Mechanistically, activation of Ang II type 1 receptor/phospholipase Cγ 1/ERK1/2 signaling resulted in a decrease of KLF15 expression. In conclusion, these results demonstrate that KLF15 negatively regulates activation of AFs through TAD, which plays an important role in Ang II-induced adventitial inflammation and fibrosis.-Lu, Y.-Y., Li, X.-D., Zhou, H.-D., Shao, S., He, S., Hong, M.-N., Liu, J.-C., Xu, Y.-L., Wu, Y.-J., Zhu, D.-L., Wang, J.-G., Gao, P.-J. Transactivation domain of Krüppel-like factor 15 negatively regulates angiotensin II-induced adventitial inflammation and fibrosis.
['Lu|Yuan-Yuan|YY|', 'Li|Xiao-Dong|XD|', 'Zhou|Han-Dan|HD|', 'Shao|Shuai|S|', 'He|Shun|S|', 'Hong|Mo-Na|MN|', 'Liu|Jia-Chen|JC|', 'Xu|Ying-Le|YL|', 'Wu|Yong-Jie|YJ|', 'Zhu|Ding-Liang|DL|', 'Wang|Ji-Guang|JG|', 'Gao|Ping-Jin|PJ|']
D063194:Adventitia D000804:Angiotensin II D000818:Animals D002465:Cell Movement D002478:Cells, Cultured D018932:Chemokine CCL2 D003094:Collagen D005347:Fibroblasts D005355:Fibrosis D057809:HEK293 Cells D006801:Humans D007249:Inflammation D051741:Kruppel-Like Transcription Factors D020935:MAP Kinase Signaling System D008264:Macrophages D008297:Male D051379:Mice D008810:Mice, Inbred C57BL D019950:Mitogen-Activated Protein Kinase 1 D048052:Mitogen-Activated Protein Kinase 3 D009000:Monocytes D000072417:Protein Domains D000067996:RAW 264.7 Cells D051381:Rats D017207:Rats, Sprague-Dawley D051785:Smad Proteins D019010:Vascular Cell Adhesion Molecule-1
KLF15 Ang II macrophage vascular remodeling adenovirus