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

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

doi:10.1172/jci.insight.141673

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.

Highlights

Abdominal aortic aneurysm (AAA) is an irreversible degenerative disease, and its rupture has a mortality rate up to 90% [1, 2]
In the elastase model (Figure 1, A and B), the progressive increase in the internal diameter of the infrarenal aorta was directly associated with a time-dependent reduction in endothelial Krüppel-like factor 11 (KLF11) expression as assessed by en face immunofluorescence staining (Figure 1C)
We demonstrated that endothelial KLF11 acts as a vasoprotective factor against AAA through multifaceted mechanisms that include reduction of inflammatory response, inhibition of matrix metallopeptidase 9 (MMP9) expression, and suppression of NOX2-mediated ROS production in endothelial cell (EC), as well as the preservation of vascular smooth muscle cell (VSMC) contractile phenotype and viability

Summary

Introduction

Abdominal aortic aneurysm (AAA) is an irreversible degenerative disease, and its rupture has a mortality rate up to 90% [1, 2]. AAA develops because of a combination of vascular inflammation, excessive oxidative stress, and maladaptive aortic wall remodeling [2, 3]. Prolonged exposure to cardiovascular risk factors, like smoking, hyperlipidemia, and proinflammatory factors, induces endothelial cell (EC) dysfunction and subsequently exacerbates vascular diseases, such as vascular inflammation [6] and atherosclerosis [5]. Endothelial dysfunction has been found to trigger vascular remodeling by releasing proteases or recruiting immune cells into the medial layer [8, 9]. Investigation of EC dysfunction and the interaction between the endothelium and medial smooth muscle cells (SMCs) during AAA development may provide a deeper understanding of AAA pathology toward novel targeted interventions

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Conclusion