Abstract

We are applying for the renewal of our grant, continuously supported by NHLBI for about 47 years.
The Aims stem from our initial investigations of enzymes that metabolize peptides such as bradykinin (BK), angiotensins and others. lilhibitors of angiotensin I converting enzyme (kininase II;ACE) are currently used to treat millions of patients with hypertension and various cardiovascular diseases. Although their therapeutic actions were thought to be due solely to blocking the generation of hypertensive angiotensin I and inactivation of hypotensive BK, ACE inhibitors enhance the effect of BK and its ACE-resistant peptide analogues on their receptors (B2, B1) by indirect and direct modes of actions.

Public Health Relevance

Angiotensin I-converting enzyme (ACE) releases the hypertensive peptide angiotensin II, but inactivates the hypotensive peptide bradykinin, as characterized by us. Worldwide, 40-50 million patients suffering from high blood pressure, heart or kidney diseases are treated with ACE inhibitors. The aims of this study are to decipher the cellular, subcellular and molecular mode of actions of ACE inhibitors exerted via bradykinin peptide receptors and thereby further our understanding of the beneficial effects of these important therapeutic agents.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
2R01HL036473-22A2
Application #
7728646
Study Section
Hypertension and Microcirculation Study Section (HM)
Program Officer
Barouch, Winifred
Project Start
1993-09-30
Project End
2011-08-31
Budget Start
2009-09-01
Budget End
2010-08-31
Support Year
22
Fiscal Year
2009
Total Cost
$392,500
Indirect Cost

  Institution

Name
University of Illinois at Chicago
Department
Pharmacology
Type
Schools of Medicine
DUNS #
098987217
City
Chicago
State
IL
Country
United States
Zip Code
60612

  Publications

Huan, Tianxiao; Joehanes, Roby; Schurmann, Claudia et al. (2016) A whole-blood transcriptome meta-analysis identifies gene expression signatures of cigarette smoking. Hum Mol Genet 25:4611-4623
Lowry, Jessica L; Brovkovych, Viktor; Zhang, Yongkang et al. (2013) Endothelial nitric-oxide synthase activation generates an inducible nitric-oxide synthase-like output of nitric oxide in inflamed endothelium. J Biol Chem 288:4174-93
Zhang, Xianming; Lowry, Jessica L; Brovkovych, Viktor et al. (2012) Characterization of dual agonists for kinin B1 and B2 receptors and their biased activation of B2 receptors. Cell Signal 24:1619-31
Brovkovych, Viktor; Zhang, Yongkang; Brovkovych, Svitlana et al. (2011) A novel pathway for receptor-mediated post-translational activation of inducible nitric oxide synthase. J Cell Mol Med 15:258-69
Erdös, Ervin G; Tan, Fulong; Skidgel, Randal A (2010) Angiotensin I-converting enzyme inhibitors are allosteric enhancers of kinin B1 and B2 receptor function. Hypertension 55:214-20
Skidgel, Randal A; Erdos, Ervin G (2007) Structure and function of human plasma carboxypeptidase N, the anaphylatoxin inactivator. Int Immunopharmacol 7:1888-99
Keil, Cora; Maskos, Klaus; Than, Manuel et al. (2007) Crystal structure of the human carboxypeptidase N (kininase I) catalytic domain. J Mol Biol 366:504-16
Chen, Zhenlong; Deddish, Peter A; Minshall, Richard D et al. (2006) Human ACE and bradykinin B2 receptors form a complex at the plasma membrane. FASEB J 20:2261-70
Stanisavljevic, Sinisa; Ignjatovic, Tatjana; Deddish, Peter A et al. (2006) Angiotensin I-converting enzyme inhibitors block protein kinase C epsilon by activating bradykinin B1 receptors in human endothelial cells. J Pharmacol Exp Ther 316:1153-8
Hecquet, Claudie; Biyashev, Dauren; Tan, Fulong et al. (2006) Positive cooperativity between the thrombin and bradykinin B2 receptors enhances arachidonic acid release. Am J Physiol Heart Circ Physiol 290:H948-58

Showing the most recent 10 out of 77 publications