Abstract 103: Vascular Smooth Muscle Cell PGC1alpha Deletion is Atheroprotective in vivo

Abstract

Introduction: In vivo studies found H 2 O 2 leads to lipid oxidation in the arterial wall and atherosclerosis formation. Catalase overexpression was found to reduce the development of aortic atherosclerosis. In vitro studies demonstrated effective transcriptional control of catalase expression through a PPARgamma coactivator 1-alpha (PGC1α)-mediated signaling cascade in the setting of ANG II exposure. Here we sought to characterize in vivo the role of PGC1α as a regulator in atherosclerosis formation. Methods: All mice were homozygous for floxed PGC1α. In addition, littermates were either knockin for SM22-Cre (PGC1α SMC-/- ) or Cre-negative (PGC1α SMC+/+ ). A retro-orbital injection of rAAV8 vectors carrying gain-of-function PCSK9 was given to 10-week-old PGC1α SMC-/- (7 M) and PGC1α SMC+/+ (9 M) mice. Mice were fed with high-fat diet and received SQ ANG II at 0.75 mg/kg/day over 6 weeks. Descending thoracoabdominal and ascending thoracic aorta atherosclerotic lesions were assessed en face and with microscopy, respectively. Catalase expression was assessed by WB in isolated MASMs and IHC staining of aortic cross-sections. Statistical significance was determined by t test. Results: When comparing PGC1α SMC-/- and PGC1α SMC+/+ mice, we found no significant difference in baseline SBP, hypertensive response to Ang II and serum LDL levels. PGC1α SMC-/- mice had significantly less thoracoabdominal aorta atherosclerosis formation (Figure A and B). PGC1α SMC-/- MASMs showed increased catalase protein expression (Figure C) but no difference in ROS production at baseline. After ANG II stimulation, PGC1α SMC-/- MASMs were noted to have decreased ROS production. IHC confirmed increased catalase staining in the tunica media of PGC1α SMC-/- mice, which was more evident after ANG II infusion for 14 days (Figure D). Conclusion: Vascular SMC PGC1α deletion leads to increased expression of catalase with a subsequent decrease in ANG II-induced atherosclerosis formation in vivo.