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Angiotensin Converting Enzyme (ACE)
ACE is a zinc-dependent dicarboxypeptidase that is responsible for the hydrolysis of angiotensin I to angiotensin II. ACE also cleaves several other peptides. Kenneth Bernstein, MD first started working on the ACE protein in 1986 and headed one of the two groups that cloned the ACE gene in 1988/1989. This work demonstrated that, while ACE is a single polypeptide chain, it is composed of two homologous catalytic domains, each of which is independently catalytic. These domains are now called the N-domain and the C-domain. One important goal of Bernstein’s research is to understand the precise and unique function of each ACE domain. Two mouse strains created by Bernstein, with point mutations introduced into the ACE gene that selectively inactivate either the ACE N- or C-domain, have proven to be a major resource in studying these functions. These mice, termed N-KO and C-KO, have been used to show that the two ACE domains are not equivalent in biological function.
The Bernstein Laboratory studies how ACE and other components of the renin-angiotensin system affect blood pressure.One of the major products of ACE catalytic activity is the peptide angiotensin II, one of the central regulators of blood pressure. Bernstein Laboratory recently studied the blood pressure response of N-KO and C-KO mice during a two-week infusion of excess angiotensin II, which demonstrated a very different blood pressure response of N-KO and C-KO mice compared to wild type (WT) mice. Such studies emphasize the unique biological function of each of the two ACE domains.
Role of ACE in the Immune Response
Bernstein Laboratory created mice overexpressing ACE in macrophages and macrophage-like cells. These animals, termed ACE 10/10, were developed to study the role of macrophage ACE in the development of atherosclerosis. By serendipity, the lab discovered that these mice appear resistant to the growth of tumor cells, and that the resistance of the 10/10 mice is immunologically mediated. Recent studies have also shown that ACE 10/10 mice have enhanced immune resistance to infection by either L. monocytogenes or methicillin-resistant S. aureus (MRSA). These findings have stimulated a new research initiative addressing the possibility of manipulating ACE to regulate immune function.
The Bernstein Laboratory has also completed studies to determine whether the increased effectiveness of ACE 10/10 macrophages will prevent the deposition of amyloid plaques in animal models of Alzheimer’s disease. The data indicate that increased ACE expression by macrophages leads to decreased soluble levels of pathogenic Aβ1-42, decreased cerebral plaques and retained cognitive function.
MHC Class I Peptide Processing
Xiao (Gregory) Shen, MD, used mice having normal, high, or no ACE to demonstrate that this enzyme plays a very significant role in the trimming of peptides presented by MHC class I molecules. Such peptides are central to the immune response. Shen’s findings were published in the science journal Nature Immunology.