Role of adipocyte angiotensinogen or angiotensin type 1a receptors in the development of diet-induced atherosclerosis or angiotensin II-induced abdominal aortic aneurysms

Objective Adipocytes express renin–angiotensin system (RAS) components, including angiotensinogen ( Agt ), the precursor to angiotensin II (AngII), and the angiotensin type 1a receptor ( AT1aR ). The RAS contributes to atherosclerosis, and AngII infusion causes abdominal aortic aneurysm (AAA) formation. We studied effects of adipocyte Agt or AT1aR deficiency on diet-induced atherosclerosis and AngII-induced AAAs in male low-density lipoprotein receptor ( Ldlr )-deficient mice. Methods For atherosclerosis, adipocyte Agt- or AT1aR -deficient Ldlr -deficient mice and littermate controls were fed a Western diet for 3 months. For AAAs, adipocyte Agt- or AT1aR -deficient Ldlr ^−/− mice and littermate controls were fed a Western diet and infused with AngII (1000 ng/kg/min) for 28 days. Atherosclerosis was quantified en face in the aortic arch by the percent of intimal surface area covered by an atherosclerotic lesion. Serum (cholesterol, triglyceride) and plasma renin activity were quantified at study end point. AAAs were quantified in vivo by ultrasound quantification of abdominal aortic lumen diameters in anesthetized mice or at study end point by quantifying maximal external abdominal aortic diameter and AAA incidence (percent). Systolic blood pressure was quantified in AngII-infused mice by tail cuff plethysmography. Adipocyte size was quantified in tissue sections of white adipose tissue. Male Ldlr ^−/− mice were fed a standard diet or a Western diet (1 or 3 months) and Agt or AT1aR messenger RNA (mRNA) abundance quantified in periaortic fat (PAF) by reverse transcriptase polymerase chain reaction. Results There was no effect of adipocyte Agt deficiency on body weight, serum cholesterol concentrations, or atherosclerotic lesions of Western diet-fed Ldlr ^−/− mice. Adipocyte Agt deficiency had no effect on body weight, serum cholesterol concentrations, abdominal aortic lumen diameter, AAA incidence, or atherosclerosis of AngII-infused Ldlr ^−/− mice. There was no effect of adipocyte AT1aR deficiency on body weight, serum cholesterol concentrations, or atherosclerotic lesions of Western diet-fed Ldlr ^−/− mice. Control, but not adipocyte AT1aR -deficient mice lost weight during AngII infusion. The size of adipocytes in white adipose tissue was increased in adipocyte AT1aR -deficient mice with no significant influences on abdominal aortic lumen diameter, AAA incidence, or atherosclerosis of AngII-infused mice. In mice fed a Western diet for 1 or 3 months, Agt mRNA abundance in abdominal PAF increased over time in both diet groups, with modest diet-induced decreases in thoracic PAF Agt mRNA abundance. There was an effect of diet duration on AT1aR mRNA abundance in thoracic PAF, and an interaction between diet and time on abdominal PAF AT1aR mRNA abundance. Conclusions Adipocyte Agt or AT1aR deficiency had minimal effects on atherosclerosis or AngII-induced AAAs. However, adipocyte AT1aR -deficient mice exhibited increased adipocyte size. Western diet-induced regulation of Agt or AT1aR mRNA abundance in PAF may have contributed to these findings. Clinical Relevance These studies address the role of components of the renin–angiotensin system (RAS), namely, angiotensinogen and angiotensin type 1a receptors, within adipocytes on experimental disease models of atherosclerosis and abdominal aortic aneurysms. Adipocytes express these RAS components and dysfunctional adipose tissue in humans has been linked both to atherosclerosis and abdominal aortic aneurysm severity. Our findings do not support a major role for these adipocyte RAS components in either disease model. Thus, although drugs targeting the RAS may be beneficial in the treatment of these disorders, they are likely not more effective in the obese population experiencing either of these disorders.