Abstract 18734: KLF4 Regulates Aortic Aneurysm Morphology and Deletion Attenuates Aortic Aneurysm Formation

Abstract

Objective: Kruppel-like Factor 4 (KLF4) is known to play a role in inducing phenotypic modulation of smooth muscle cells (SMC) following ischemia reperfusion injury and in atherosclerosis; however, its role in aortic aneurysms (AA) remains unknown. The study objective was to evaluate the role of genetic deletion of KLF4 on development of experimental AAs. Methods: 8-12 week male (n=12) KLF4 flx/wt ERT tamoxifen Cre+ mice (“KLF4 conditional het KO mice”) and KLF4 flx/wt ERT tamoxifen Cre- (WT) mice underwent elastase perfusion following tamoxifen injection. In separate experiments, 8-12 week male (n=13) KLF4 flx/flx Smooth muscle myosin heavy chain (Myh11) Cre+(“SMC specific conditional KLF4 KO mice”), and KLF4 wt/wt SM-MHC Cre+ (“Myh11 Cre WT”) underwent elastase perfusion following tamoxifen administration. At 14 days, maximal aortic dilation was measured with video micrometry. Aortic samples were evaluated with histology for α-actin, macrophages, neutrophils, T lymphocytes and elastin. Results: Maximal aortic dilation was significantly reduced in KLF4 conditional het KO mice compared to WT controls (42.9 ± 7.3% versus 78.9 ± 12.6%, p<0.039). In addition, these mice had reduced macrophage and neutrophil infiltration with greater elastin preservation and α-actin expression. SMC specific conditional KLF4 KO mice also showed a significant reduction in aortic dilation following elastase perfusion as compared to Myh11 Cre+ WT controls (53.4 ± 7.76% versus 93.8 ± 16.2%, p<0.028). These mice also had reduced macrophage and neutrophil staining and increased elastin preservation and α-actin expression. Conclusions: KLF4 plays a critical role in promoting AA formation, since heterozygous KLF4 KO mice showed reduced aneurysm formation. At least part of this effect is due to loss of KLF4 in SMC since SMC specific conditional KLF4 KO mice also showed reduced AA formation as well as decreased immune cell recruitment and greater preservation of elastin and SMCs. Taken together, results identify KLF4 as a novel therapeutic target for treatment of aneurysms.