Abstract 517: Effect of Hepatocyte-specific Depletion of AT1a Receptors on Atherosclerosis and Aneurysms
Background and Objective Whole body deficiency of AT1a receptors (AT1aRs) ablates angiotensin II (AngII) induced vascular pathologies that include aortic aneurysms and atherosclerosis. We created AT1aR floxed mice to determine the role of specific cell types expressing this receptor on these vascular pathologies. Unexpectedly, these mice demonstrated a lack of effect of smooth muscle specific AT1aR deficiency on the development of atherosclerosis or aneurysms. Also, endothelial-specific AT1aR deficiency had no effect in atherosclerosis and minimal effect on aneurysms. The purpose of this study was to determined if AngII infusion was releasing substances from the liver that influence vascular pathology.
Methods and Results Hepatocyte depletion of AT1aRs was accomplished using two methods of introducing Cre into AT1aR floxed mice. One approach was injection of adenovirus Cre (AdCre) and the other by breeding to mice expressing Cre under the control of the albumin promoter. To induce atherosclerosis, groups of wild type and hepatocyte-specific AT1aR depleted male (N=15-21/group) and female (N=21/group) mice were fed a saturated fat enriched diet for 12 weeks. Hepatocyte-specific depletion of AT1aRs was confirmed using detection of Cre and absence of AT1aRs by PCR and RT-PCR, respectively. Body weights, serum cholesterol concentrations, and systemic blood pressures were not different between wild type and hepatocyte-specific AT1aR depleted mice grouped by gender and genotype. Atherosclerotic burden was similar in all groups. To examine AngII-induced atherosclerosis, male wild type and hepatocyte-specific AT1aR depleted mice (N=11-16/group) were fed a fat enriched diet for 5 weeks, and AngII (1,000 mg/kg/min) was infused using osmotic mini-pumps for 28 days. AngII infusion increased systolic blood pressure, promoted atherosclerosis and induced aneurysms to a similar degree in both genotypes.
Conclusion Deletion of hepatocyte-specific AT1aRs did not affect dietary or AngII-induced vascular pathologies.
- © 2013 by American Heart Association, Inc.