Abstract 16881: Endothelial KLF11 is a Novel Endogenous Protectant Against Diabetic Atherosclerosis

Background: Atherosclerosis is the leading cause of cardiovascular diseases, which is also the primary cause of mortality among diabetic patients. Endothelial cell (EC) dysfunction is a critical early step in the development of atherosclerosis and aggravated in the presence of concurrent diabetes. Krüppel like factor 11 (KLF11), a transcription factor involved in diabetes, inhibits EC inflammation via regulation of NF-κB signaling. However, the potential function of KLF11 in pathogenesis of diabetic atherosclerosis remains undefined.

Methods and results: Diet-induced type 2 diabetic atherosclerosis model is established in LDLR ^-/- mice by feeding a diabetogenic high-fat diet with cholesterol (DDC). KLF11 expression was increased in ECs from ascending aorta of LDLR ^-/- mice fed DDC diet. Moreover, EC specific KLF11 gain- (transgenic) and loss-of-function (knockout) mice in a LDLR ^-/- background were fed a DDC for 16 weeks. Endothelial KLF11 deficiency (Klf11 ^ECKO -LDLR ^-/- ) markedly increased atherogenesis, while EC-selective KLF11 overexpression significantly inhibited DDC-induced atherogenesis. Single cell RNA sequencing profiling the ECs isolated from DDC-fed Klf11 ^ECKO -LDLR ^-/- mice and littermate controls showed that KLF11 depletion increased endothelial-to-mesenchymal transition (EndMT) during atherogenesis. In vitro studies showed that KLF11 not only inhibited EC inflammation and oxidative stress, but also diminished EndMT in response to high glucose. Conversely, knockdown of KLF11 augmented the EC dysfunction and EndMT.

Conclusions: Our study indicates that endothelial KLF11 protects against diabetic atherosclerosis through inhibition of EC inflammation, oxidative stress and EndMT.