Angiotensin converting enzyme-2 (ACE-2) catabolizes angiotensin II (Angll) to form the vasodilator Angiotensin1-7 (Ang1-7). The sponsor's laboratory has demonstrated that Angll increases atherosclerotic lesions and induces formation of abdominal aortic aneurysms (AAAs) in hyperlipidemic mice. Preliminary data generated by the applicant demonstrates ACE2 expression in macrophages and localization to atherosclerotic and AAA lesions. ACE2 has been implicated in blood pressure regulation, however, it is unclear whether dysregulated ACE2 contributes to Angll-induced vascular diseases. The long term objective of this study is to understand the role of ACE-2 in the development of atherosclerotic lesions and in Angll-induced AAA formation. Since macrophages are key mediators in developing atherosclerotic lesions and AAAs, we will focus on macrophage ACE2 as a regulator of Angll-induced vascular diseases. The following specific aims will address our goal: 1) determine the effect of whole-body and/or bone marrow-derived ACE2 deficiency on hypercholesterolemia-induced atherosclerosis in low density lipoprotein receptor (LDLr) -/- mice;2) determine the effect of whole body and/or bone marrow-derivedACE2 deficiency on Angll-induced AAAs in LDLr-/- mice.
In aim 1, we will first examine the effect of ACE2 deficiency in LDLr-/- mice on high fat diet-induced atherosclerosis. Additional studies will use chimeric LDLr-/- mice repopulated with bone marrow from ACE2-/y mice to define the role of leukocytes in hypercholesterolemia-induced atherosclerosis. Mechanisms for ACE2 regulation by hypercholesterolemia will be examined using mouse peritoneal macrophages.
In aim 2, we will define effects of ACE2 deficiency in LDLr-/- mice on Angll-induced AAAs, and in follow up studies determine effects of ACE2 deficiency in bone marrow-derived cells on AAA formation. The relevance of the proposed research is to define mechanisms contributing to the development of two different types of common vascular diseases that negatively impact the health of millions of Americans. Identification of a regulatory role of the enzymeACE2 in Angll-induced atherosclerosis and AAAs may lead to novel medical therapies for these cardiovascular diseases.
|Thatcher, Sean E; Zhang, Xuan; Howatt, Deborah A et al. (2014) Angiotensin-converting enzyme 2 decreases formation and severity of angiotensin II-induced abdominal aortic aneurysms. Arterioscler Thromb Vasc Biol 34:2617-23|
|Gupte, Manisha; Thatcher, Sean E; Boustany-Kari, Carine M et al. (2012) Angiotensin converting enzyme 2 contributes to sex differences in the development of obesity hypertension in C57BL/6 mice. Arterioscler Thromb Vasc Biol 32:1392-9|
|Thatcher, Sean E; Zhang, Xuan; Howatt, Deborah A et al. (2011) Angiotensin-converting enzyme 2 deficiency in whole body or bone marrow-derived cells increases atherosclerosis in low-density lipoprotein receptor-/- mice. Arterioscler Thromb Vasc Biol 31:758-65|