Overexpression of myeloid angiotensin-converting enzyme (ACE) reduces atherosclerosis

• Type of Material: Article
• Authors: Derick Okwan-Duodu, Cedars-Sinai Medical Center; Daiana Weiss, Emory University; Zhenzi Peng, Cedars-Sinai Medical Center; Luciana Veiras, Cedars-Sinai Medical Center; Duo-Yao Cao, Cedars-Sinai Medical Center; Suguru Saito, Cedars-Sinai Medical Center; Zakir Khan, Cedars-Sinai Medical Center; Ellen A. Bernstein, Cedars-Sinai Medical Center; Jorge F. Giani, Cedars-Sinai Medical Center; W. Robert Taylor, Emory University; Kenneth Bernstein, Emory University
• Language: English
• Date: 2019-12-10
• Publisher: ACADEMIC PRESS INC ELSEVIER SCIENCE
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: 2019
• License: Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1016/j.bbrc.2019.10.078
• Title of Journal or Parent Work: BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS
• Volume: 520
• Issue: 3
• Start Page: 573
• End Page: 579
• Grant/Funding Information: This work was supported by NIH P01 HL095070 (WRT), P01HL129941 (KEB), R01AI134714 (KEB) and K99HL141638 (DOD).
• Keywords: Biochemistry & Molecular Biology; CELLS; Myeloid cells; Life Sciences & Biomedicine; Hypertension; Atherosclerosis; RESISTANT; Science & Technology; MACROPHAGES; EXPRESSION; Biophysics; Inflammation; Angiotensin-converting enzyme; MICE; PROGRESSION
• Research Categories: Health Sciences, Immunology; Biophysics, General

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 ACE10/10ApoE−/− (ACE10/ApoE). Control mice were ACEWT/WTApoE−/− (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 ACE10/10 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.