Abstract
Angiotensin-converting enzyme (ACE) plays an important role in blood pressure control. ACE also has effects on renal function, reproduction, hematopoiesis, and several aspects of the immune response. ACE 10/10 mice overexpress ACE in monocytic cells; macrophages from ACE 10/10 mice demonstrate increased polarization toward a proinflammatory phenotype. As a result, ACE 10/10 mice have a highly effective immune response following challenge with melanoma, bacterial infection, or Alzheimer disease. As shown in ACE 10/10 mice, enhanced monocytic function greatly contributes to the ability of the immune response to defend against a wide variety of antigenic and non-antigenic challenges.
Acknowledgments
The authors acknowledge the tireless support of Mr. Brian Taylor. This study was supported by the National Institute of Health grants grants R01 HL110353, T32 DK007770, and R00 HL088000; by Beginning Grant-in-Aid 13BGIA14680069 and Scientist Development Grant 11SDG6770006 from the American Heart Association; by the Coins for Alzheimer’s Research Trust (CART) Fund; by the BrightFocus Foundation (former AHAF), the Maurice Marciano Family Foundation, and the National Center for Advancing Translational Sciences through CTSI Grant UL1TR000124. The authors dedicate the manuscript to the memory of Natalie Radom Bernstein who died on April 9, 2013, and Salomon Moni Hamaoui who died on March 6, 1994, both of Alzheimer disease.
References
Bernstein, K.E., Ong, F.S., Blackwell, W.L., Shah, K.H., Giani, J.F., Gonzalez-Villalobos, R.A., Shen, X.Z., and Fuchs, S. (2013). A modern understanding of the traditional and nontraditional biological functions of angiotensin-converting enzyme. Pharmacol. Rev. 65, 1–46.Search in Google Scholar
Bernstein, K.E., Koronyo, Y., Salumbides, B.C., Sheyn, J., Pelissier, L., Lopes, D.H.J., Shah, K.H., Bernstein, E.A., Fuchs, D.-T., Yu, J.J., et al. (2014). Angiotensin-converting enzyme overexpression in myelomonocytes prevents Alzheimer’s-like cognitive decline. J. Clin. Invest. 124, 1000–1012.Search in Google Scholar
Cole, J., Ertoy, D., Lin, H., Sutliff, R.L., Ezan, E., Guyene, T.T., Capecchi, M., Corvol, P., and Bernstein, K.E. (2000). Lack of angiotensin II-facilitated erythropoiesis causes anemia in angiotensin-converting enzyme-deficient mice. J. Clin. Invest. 106, 1391–1398.Search in Google Scholar
Corvol, P., Eyries, M., and Soubrier, F. (2004). Peptidyl-dipeptidase A/Angiotensin I-converting enzyme. In: Handbook of Proteolytic Enzymes, A. Barret, N. Rawlings, and J. Woessner, eds. (New York: Elsevier Academic Press), pp. 332–349.Search in Google Scholar
Esther, C.R. Jr., Howard, T.E., Marino, E.M., Goddard, J.M., Capecchi, M.R., and Bernstein, K.E. (1996). Mice lacking angiotensin-converting enzyme have low blood pressure, renal pathology, and reduced male fertility. Lab. Invest. 74, 953–965.Search in Google Scholar
Gordon, S. and Taylor, P.R. (2005). Monocyte and macrophage heterogeneity. Nat. Rev. Immunol. 5, 953–964.Search in Google Scholar
Krege, J.H., John, S.W., Langenbach, L.L., Hodgin, J.B., Hagaman, J.R., Bachman, E.S., Jennette, J.C., O’Brien, D.A., and Smithies, O. (1995). Male-female differences in fertility and blood pressure in ACE-deficient mice. Nature 375, 146–148.Search in Google Scholar
Kurata, A., Terado, Y., Schulz, A., Fujioka, Y., and Franke, F.E. (2005). Inflammatory cells in the formation of tumor-related sarcoid reactions. Hum. Pathol. 36, 546–554.Search in Google Scholar
Lin, C., Datta, V., Okwan-Duodu, D., Chen, X., Fuchs, S., Alsabeh, R., Billet, S., Bernstein, K.E., and Shen, X.Z. (2011). Angiotensin-converting enzyme is required for normal myelopoiesis. FASEB J. 25, 1145–1155.Search in Google Scholar
Maiolino, G., Rossitto, G., Caielli, P., Bisogni, V., Rossi, G.P., and Calò, L.A. (2013). The role of oxidized low-density lipoproteins in atherosclerosis: the myths and the facts. Mediators Inflamm. 2013, 714653.Search in Google Scholar
Mantovani, A., Sica, A., Sozzani, S., Allavena, P., Vecchi, A., and Locati, M. (2004). The chemokine system in diverse forms of macrophage activation and polarization. Trends Immunol. 25, 677–686.Search in Google Scholar
Okwan-Duodu, D., Datta, V., Shen, X.Z., Goodridge, H.S., Bernstein, E.A., Fuchs, S., Liu, G.Y., and Bernstein, K.E. (2010). Angiotensin-converting enzyme overexpression in mouse myelomonocytic cells augments resistance to Listeria and methicillin-resistant Staphylococcus aureus. J. Biol. Chem. 285, 39051–39060.Search in Google Scholar
Selkoe, D.J. (2008). Soluble oligomers of the amyloid β-protein impair synaptic plasticity and behavior. Behav. Brain Res. 192, 106–113.Search in Google Scholar
Shen, X.Z., Li, P., Weiss, D., Fuchs, S., Xiao, H.D., Adams, J.W., Williams, I.R., Capecchi, M.R., Taylor, W.R., and Bernstein, K.E. (2007). Mice with enhanced macrophage angiotensin converting enzyme are resistant to melanoma. Am. J. Pathol. 170, 2122–2134.Search in Google Scholar
Shen, X.Z., Billet, S., Lin, C., Okwan-Duodu, D., Chen, X., Lukacher, A.E., and Bernstein, K.E. (2011). The carboxypeptidase ACE shapes the MHC class I peptide repertoire. Nat. Immunol. 12, 1078–1085.Search in Google Scholar
Yu, X.H., Fu, Y.C., Zhang, D.W., Yin, K., and Tang, C.K. (2013). Foam cells in atherosclerosis. Clin. Chim. Acta 424, 245–252.Search in Google Scholar
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