Abstract 12993: Hepatocyte-Specific Angiotensinogen Deficiency Markedly Reduces Hypercholesterolemia-Induced Atherosclerosis and Diet-Induced Obesity in Mice
Background and Objective: We previously developed angiotensinogen (AGT) hypomorphic mice in an LDLr −/− background and demonstrated that whole body reduction of AGT profoundly reduced hypercholesterolemia-induced atherosclerosis. AGT can be synthesized in many cell types with hepatocytes considered to be a major source. To determine the contribution of hepatocyte-derived AGT to the development of atherosclerosis, we generated LDLr −/− mice with hepatocyte-specific deficiency of AGT (hepAGT −/−).
Methods and Results: Floxed AGT mice were developed with no overt phenotype. hepAGT −/− mice were generated by breeding AGT floxed mice with transgenic mice expressing Cre under the control of albumin promoter. All mice were on LDLr −/− background. Male hepAGT +/+ (n=9) and −/− (n =8) littermates were fed a diet enriched in saturated fat (21% wt/wt milk fat) for 12 weeks. Hepatocyte-specific AGT deficiency strikingly reduced plasma concentrations of AGT (hepAGT +/+ and −/−: 2292 ± 266 versus 117 ± 28 ng/ml; p < 0.001). Hepatocyte-specific deficiency also greatly reduced systolic blood pressure (145 ± 7 versus 104 ± 6 versus mmHg; p < 0.01). Both groups were hypercholesterolemic with no difference in plasma total cholesterol concentrations. Atherosclerosis was determined by en face measurement of percent intimal area covered by lesions. Hepatocyte-specific AGT deficiency profoundly reduced the percent of intima area covered by atherosclerotic lesions (18.1 ± 2.3 versus 3.3 ± 0.9 %, p < 0.001). Unexpectedly, the increased body weight observed during feeding the saturated fat-enriched diet to wild type mice was ablated in hepatocyte-specific AGT deficient mice. The attenuation was attributable to a reduction in fat masses as determined by measurement of fat masses with Echo MRI. Changes in all these parameters were similar to that were observed in AGT hypomorphic mice.
Conclusions: AGT synthesized in hepatocytes is responsible for the phenotypic changes during feeding a saturated fat diet.
- © 2011 by American Heart Association, Inc.