A relatively new hypothesis is that inflammation is a critical pathologic process affecting long term blood pressure control. Also, inflammation underlies the major life-threatening negative sequellae of hypertension, including vascular and renal injury, stroke and atherosclerosis. Thus, understanding inflammation in the setting of hypertension is critical for understanding and managing the progression of hypertensive disease. Angiotensin converting enzyme (ACE) plays an important role in blood pressure control, and ACE inhibitors are in widespread clinical use. Angiotensin I and bradykinin are well known ACE substrates, but the enzyme also cleaves several other peptides. In part, this is because the ACE present in higher animals is composed of two separate and independent catalytic domains. To understand the detailed in vivo function of each catalytic domain, my group created genetically modified mice possessing only a single functioning ACE domain. We now present an analysis of a mouse model, termed N-KO, with sustained elevation of AcSDKP, due to the lack of ACE N-domain catalytic activity. These studies show that the induction of experimental hypertension in such a mouse induces a significantly higher level of blood pressure and tissue injury than in the absence of high AcSDKP levels. Further, we find that this is due to an increased inflammatory response directly induced by AcSDKP. These data provide dramatic new insight into the biological role of AcSDKP and the pathogenesis of hypertensive injury. They also offer a potential new area of intervention - the enzyme responsible for the formation of AcSDKP - that could have very practical effects in treating the inflammatory response in hypertension and many other diseases. This proposal contains three Specific Aims. The first Specific Aim is to study the whole animal hypertensive response in mice having high or low AcSDKP levels. The second Specific Aim is to study which inflammatory cells contribute to the pathogenesis of disease in these mice. The third Specific Aim is a biochemical investigation of how AcSDKP causes its physiologic effects. In proposing experiments that go from the whole animal (Aim 1) to the cellular response (Aim 2) to the biochemical mechanism of how AcSDKP works (Aim 3), we offer a comprehensive plan to investigate the physiological effects of AcSDKP. Given the very large number of people taking ACE inhibitors, and the fact that all ACE inhibitors raise AcSDKP level, it is important to understand the physiologic effects of high AcSDKP.

Public Health Relevance

Angiotensin converting enzyme (ACE) is an enzyme important in blood pressure control. By genetically altering ACE in mice, we found that an ACE substrate, the peptide acetyl- SerAspLysPro, plays an important regulatory role in the inflammatory response observed in a model of hypertension. This proposal investigates the mechanisms by which ACE and acetyl- SerAspLysPro affect the inflammatory response and may yield ways to prevent hypertensive injury to blood vessels and the kidney.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL110353-28
Application #
8676928
Study Section
Hypertension and Microcirculation Study Section (HM)
Program Officer
Maric-Bilkan, Christine
Project Start
1988-04-01
Project End
2016-05-31
Budget Start
2014-06-01
Budget End
2015-05-31
Support Year
28
Fiscal Year
2014
Total Cost
$416,521
Indirect Cost
$167,054
Name
Cedars-Sinai Medical Center
Department
Type
DUNS #
075307785
City
Los Angeles
State
CA
Country
United States
Zip Code
90048
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Khan, Zakir; Shen, Xiao Z; Bernstein, Ellen A et al. (2017) Angiotensin-converting enzyme enhances the oxidative response and bactericidal activity of neutrophils. Blood 130:328-339
Giani, Jorge F; Eriguchi, Masahiro; Bernstein, Ellen A et al. (2017) Renal tubular angiotensin converting enzyme isĀ responsible for nitro-L-arginine methyl esterĀ (L-NAME)-induced salt sensitivity. Kidney Int 91:856-867
Zhao, Tuantuan; Bernstein, Kenneth E; Fang, Jianmin et al. (2017) Angiotensin-converting enzyme affects the presentation of MHC class II antigens. Lab Invest 97:764-771
Itani, Hana A; Xiao, Liang; Saleh, Mohamed A et al. (2016) CD70 Exacerbates Blood Pressure Elevation and Renal Damage in Response to Repeated Hypertensive Stimuli. Circ Res 118:1233-43
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Itani, Hana A; McMaster Jr, William G; Saleh, Mohamed A et al. (2016) Activation of Human T Cells in Hypertension: Studies of Humanized Mice and Hypertensive Humans. Hypertension 68:123-32
Garcia, Victor; Joseph, Gregory; Shkolnik, Brian et al. (2015) Angiotensin II receptor blockade or deletion of vascular endothelial ACE does not prevent vascular dysfunction and remodeling in 20-HETE-dependent hypertension. Am J Physiol Regul Integr Comp Physiol 309:R71-8
Shah, Kandarp H; Shi, Peng; Giani, Jorge F et al. (2015) Myeloid Suppressor Cells Accumulate and Regulate Blood Pressure in Hypertension. Circ Res 117:858-69
Shen, Xiao Z; Li, You; Li, Liang et al. (2015) Microglia participate in neurogenic regulation of hypertension. Hypertension 66:309-16

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