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.

BAF60c prevents abdominal aortic aneurysm formation through epigenetic control of vascular smooth muscle cell homeostasis

“…The elastase-induced AAA model was implemented as previously described ( 54 , 55 ). In brief, 10- to 12-week-old male Baf60c SMKO and Baf60c fl/fl mice were anesthetized by intraperitoneal injection of a mixture of ketamine (100 mg/kg) and xylazine (5 mg/kg).…”

KLF11 Protects against Venous Thrombosis via Suppressing Tissue Factor Expression

“…The procedures were performed as previously described. 13 14 In brief, after 48-hour ligation-induced DVT or sham operation, murine vessels (IVC + abdominal aorta) were collected, fixed in 4% paraformaldehyde, and embedded in Tissue-Tek O.C.T. Compound.…”

“…Endothelial KLF11 has been demonstrated to maintain vascular homeostasis in many diseases, including sepsis, stroke, abdominal aortic aneurysm, and type 2 diabetes mellitus. 9 10 11 12 13 We also recently identified that selectively deficiency of KLF11 in vascular smooth muscle cells (VSMCs) aggravated arterial thrombosis formation. 14 In line with the known protective effects of KLF11 in vascular diseases, in this study, we further found that KLF11 inhibits deep vein thrombosis (DVT) formation.…”

KLF11 Is a Novel Endogenous Protectant against Renal Ischemia-Reperfusion Injury

“…We did not measure blood pressure in KLF11 +/+ and KLF11 -/mice. Prior studies demonstrate that blood pressure of KLF11 -/is not elevated under basal or stress conditions (6).…”