KLF11 protects against abdominal aortic aneurysm through inhibition of endothelial cell dysfunction
Guizhen Zhao, Ziyi Chang, Yang Zhao, Yanhong Guo, Haocheng Lu, Wenying Liang, Oren Rom, Huilun Wang, Jinjian Sun, Tianqing Zhu, Yanbo Fan, Lin Chang, Bo Yang, Minerva T. Garcia-Barrio, Y. Eugene Chen, Jifeng Zhang
Guizhen Zhao, Ziyi Chang, Yang Zhao, Yanhong Guo, Haocheng Lu, Wenying Liang, Oren Rom, Huilun Wang, Jinjian Sun, Tianqing Zhu, Yanbo Fan, Lin Chang, Bo Yang, Minerva T. Garcia-Barrio, Y. Eugene Chen, Jifeng Zhang
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Research Article Vascular biology

KLF11 protects against abdominal aortic aneurysm through inhibition of endothelial cell dysfunction

Abstract

Abdominal aortic aneurysm (AAA) is a life-threatening degenerative vascular disease. Endothelial cell (EC) dysfunction is implicated in AAA. Our group recently demonstrated that Krüppel-like factor 11 (KLF11) plays an essential role in maintaining vascular homeostasis, at least partially through inhibition of EC inflammatory activation. However, the functions of endothelial KLF11 in AAA remain unknown. Here we found that endothelial KLF11 expression was reduced in the ECs from human aneurysms and was time dependently decreased in the aneurysmal endothelium from both elastase- and Pcsk9/AngII-induced AAA mouse models. KLF11 deficiency in ECs markedly aggravated AAA formation, whereas EC-selective KLF11 overexpression markedly inhibited AAA formation. Mechanistically, KLF11 not only inhibited the EC inflammatory response but also diminished MMP9 expression and activity and reduced NADPH oxidase 2–mediated production of reactive oxygen species in ECs. In addition, KLF11-deficient ECs induced smooth muscle cell dedifferentiation and apoptosis. Overall, we established endothelial KLF11 as a potentially novel factor protecting against AAA and a potential target for intervention in aortic aneurysms.

Authors

Guizhen Zhao, Ziyi Chang, Yang Zhao, Yanhong Guo, Haocheng Lu, Wenying Liang, Oren Rom, Huilun Wang, Jinjian Sun, Tianqing Zhu, Yanbo Fan, Lin Chang, Bo Yang, Minerva T. Garcia-Barrio, Y. Eugene Chen, Jifeng Zhang

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Figure 3

EC-selective overexpression of KLF11 attenuates Pcsk9/AngII-induced AAA.

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EC-selective overexpression of KLF11 attenuates Pcsk9/AngII-induced AAA....
The Pcsk9/AngII-induced AAA model was performed on 10-week-old male EC-selective KLF11 transgenic mice (Tie2-KLF11–Tg, n = 12) and littermate control mice (WT, n = 13). (A) Representative morphology of aortas from AngII-infused WT and Tie2-KLF11–Tg mice. (B) Incidence of AAA. (C) Maximal diameters of SAAs. (D) Representative VVG staining and quantification of elastin degradation in SAAs from WT and Tie2-KLF11–Tg mice (n = 10/group). Scale bar: 200 μm for whole aortic sections, 20 μm for magnified areas. (E) Representative immunofluorescence staining and quantification of leukocyte (CD45+) and macrophage (Mac2+) infiltration in the aortic wall of SAAs from WT and Tie2-KLF11–Tg mice (n = 10/group). Scale bar: 20 μm. (F) Representative TUNEL staining (green) and quantification of apoptotic cells in the media of SAAs from WT and Tie2-KLF11–Tg mice (n = 10/group). Scale bar: 20 μm. Data are presented as mean ± SEM. χ2 test (B), Student’s 2-tailed t test (C, E, and F), Mann-Whitney U test (D).