Abstract
BACKGROUND: Macrophages are ubiquitous in all stages of atherosclerosis, exerting tremendous impact on lesion progression and plaque stability. Because macrophages in atherosclerotic plaques express angiotensin-converting enzyme (ACE), current dogma posits that local myeloid-mediated effects worsen the disease. In contrast, we previously reported that myeloid ACE overexpression augments macrophage resistance to various immune challenges, including tumors, bacterial infection and Alzheimer's plaque deposition. Here, we sought to assess the impact of myeloid ACE on atherosclerosis. METHODS: A mouse model in which ACE is overexpressed in myelomonocytic lineage cells, called ACE10, was generated and sequentially crossed with ApoE-deficient mice to create ACE(10/10)ApoE(-/-) (ACE10/ApoE). Control mice were ACE(WT/WT)ApoE(-/-) (WT/ApoE). Atherosclerosis was induced using an atherogenic diet alone, or in combination with unilateral nephrectomy plus deoxycorticosterone acetate (DOCA) salt for eight weeks. RESULTS: With an atherogenic diet alone or in combination with DOCA, the ACE10/ApoE mice showed significantly less atherosclerotic plaques compared to their WT/ApoE counterparts (p < 0.01). When recipient ApoE(-/-) mice were reconstituted with ACE(10/10) bone marrow, these mice showed significantly reduced lesion areas compared to recipients reconstituted with wild type bone marrow. Furthermore, transfer of ACE-deficient bone marrow had no impact on lesion area. CONCLUSION: Our data indicate that while myeloid ACE may not be required for atherosclerosis, enhanced ACE expression paradoxically reduced disease progression.