ACE is a dipeptidyl carboxypeptidase whose natural substrates include the oligopeptides angiotensin I and bradykinin. It has two isozymes, sACE and gACE, which have similar enzymatic activities but are expressed in a tissue-specific manner: gACE expression is restricted to developing male germ cells, whereas sACE is expressed in vascular endothelial cells, kidney tubular epithelial cells, intestinal brush border cells, monocytes and specific cell types in the brain. ACE-/- mice not only have lower blood pressure, but they also have abnormalities in kidney structure and function, and the male mice are sterile. By tissue-specific expression of transgenes encoding only one of the two isozymes of ACE, we have demonstrated that expression of sACE in the vascular endothelial cells is absolutely needed for blood pressure regulation;circulating sACE is insufficient for this function, although it can rectify the kidney problems of the Ace-/- mouse. In this application it is hypothesized that, in addition to its ability to produce angiotensin II, vascular endothelial cell-bound sACE has another activity to mediate outside-in signaling that is absolutely required for blood pressure regulation. To test this hypothesis, several transgenic sACE mutants will be expressed in Ace-/- mice using a vascular endothelial cell-specific transcriptional promoter. These transgenic studies will be complemented with tissue-specific and temporally regulated ablation of expression of the ACE gene. These studies will clearly delineate the relationships between specific physiological functions of ACE and its expression in specific tissues. The proposed molecular approach using a combination of transgenic and conditional knock-out techniques will lead to a better understanding of the basis of multiple functions of ACE and may lead to the development of clinical protocols for blocking a specific function of ACE without inhibiting others.

Public Health Relevance

Angiotensin-converting enzyme (ACE) is a clinically important enzyme whose elevated circulating levels are associated with the pathogenesis of ?essential? hypertension, heart failure and renal failure. Consequently, inhibitors of this enzyme are widely used for clinical management of these diseases. We propose to use transgenic and gene knockout approaches in mice to understand the nature of the multiple physiological functions of ACE. This knowledge will help to develop therapeutic protocols for blocking a specific function of ACE without affecting others.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
Project #
Application #
Study Section
Hypertension and Microcirculation Study Section (HM)
Program Officer
Maric-Bilkan, Christine
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Cleveland Clinic Lerner
Other Basic Sciences
Schools of Medicine
United States
Zip Code
Chattopadhyay, Saurabh; Kessler, Sean P; Colucci, Juliana Almada et al. (2014) Tissue-specific expression of transgenic secreted ACE in vasculature can restore normal kidney functions, but not blood pressure, of Ace-/- mice. PLoS One 9:e87484
Chattopadhyay, Saurabh; Karan, Goutam; Sen, Indira et al. (2008) A small region in the angiotensin-converting enzyme distal ectodomain is required for cleavage-secretion of the protein at the plasma membrane. Biochemistry 47:8335-41
Kessler, Sean P; Senanayake, Preenie deS; Gaughan, Christina et al. (2007) Vascular expression of germinal ACE fails to maintain normal blood pressure in ACE-/- mice. FASEB J 21:156-66
Chattopadhyay, Saurabh; Santhamma, Kizhakkekara R; Sengupta, Saubhik et al. (2005) Calmodulin binds to the cytoplasmic domain of angiotensin-converting enzyme and regulates its phosphorylation and cleavage secretion. J Biol Chem 280:33847-55
Kessler, Sean P; Hashimoto, Seiji; Senanayake, Preenie S et al. (2005) Nephron function in transgenic mice with selective vascular or tubular expression of Angiotensin-converting enzyme. J Am Soc Nephrol 16:3535-42
Kessler, Sean P; deS Senanayake, Preenie; Scheidemantel, Thomas S et al. (2003) Maintenance of normal blood pressure and renal functions are independent effects of angiotensin-converting enzyme. J Biol Chem 278:21105-12
Kessler, Sean P; Gomos, Janette B; Scheidemantel, Thomas S et al. (2002) The germinal isozyme of angiotensin-converting enzyme can substitute for the somatic isozyme in maintaining normal renal structure and functions. J Biol Chem 277:4271-6
Kessler, S P; Rowe, T M; Gomos, J B et al. (2000) Physiological non-equivalence of the two isoforms of angiotensin-converting enzyme. J Biol Chem 275:26259-64
Sadhukhan, R; Sen, G C; Ramchandran, R et al. (1998) The distal ectodomain of angiotensin-converting enzyme regulates its cleavage-secretion from the cell surface. Proc Natl Acad Sci U S A 95:138-43
Ramaraj, P; Kessler, S P; Colmenares, C et al. (1998) Selective restoration of male fertility in mice lacking angiotensin-converting enzymes by sperm-specific expression of the testicular isozyme. J Clin Invest 102:371-8

Showing the most recent 10 out of 23 publications