Abstract 14858: Conditional Deletion of Lysyl Oxidase Improves Vascular Function in Apoe -/- Mice

Abstract

Introduction: Lysyl oxidase (LOX) is a copper-dependent amino-oxidase that initiates covalent cross-linking of collagen and elastin, modifies growth factor action and controls gene expression. LOX upregulation is associated with cardiovascular diseases. Because embryonic LOX knockout (KO) mice die perinatally of aortic aneurysms and cardiovascular dysfunction, the studies about LOX function in cardiovascular disease has relied mostly on the use of beta-aminopropionitrile. However, this irreversible inhibitor also inhibits other members of LOX family. Hypothesis: To overcome this limitation, we hypothesized that conditional inactivation of lysyl oxidase would improve vascular function in apoE -/- mice. Methods: We developed, for the first time, a global (LOX f/f CAG-CreERT2 ApoE -/- ) and a smooth muscle cell (SMC) specific (LOX f/f Myh11-CreERT2 ApoE -/- ) LOX conditional knockout mice. Results: LOX inactivation in SMC decreased immature collagen crosslinking in the aorta, carotid pulse wave velocity and blood pressure. It led to a significant reduction in atherosclerotic plaque deposition in the aorta after 16 weeks of high-fat diet (HFD). Global inactivation of LOX, on the other hand, also reduced the systolic blood pressure and prevented vascular stiffness after 4 weeks of HFD. In in-vitro studies, we found that LOX is present in the extracellular space and the nucleus of SMC. Bulk RNA-seq revealed that LOX deletion elevated the expression of SMC alpha-actin, transgelin, and filamin A genes, which are typically present in the contractile phenotype. Conclusion: Our data show that conditional deletion of LOX is atheroprotective and improved vascular and hemodynamic function in ApoE KO mice.