We want to determine if prolylcarboxypeptidase (PRCP) is a risk factor for cardiovascular disease. PRCP degrades angiotensin II (AngII) and bradykinin 1-8. We identified that the serine protease PRCP as a cell- surface plasma prekallikrein activator independent of factor XIIa. PRCP has been predicted as a gene associated with essential hypertension. In a genome-wide association study, PRCP was identified as a risk factor for metabolic syndrome in males. A polymorphism in PRCP, E112D, was shown to be associated with preeclampsia, especially in women with a previous history of chronic hypertension. Also, the presence of this polymorphism in Han Chinese was shown to be associated with resistance to angiotensin converting enzyme inhibitor treatment for hypertension. Additionally, we showed that PRCP metabolizes a-MSH1-13 to a-MSH1-12. In mice deficient in PRCP, this activity results in reduced aMSH1-13 metabolism in the hypothalamus allowing for overstimulation of an anorexic impulse producing lean mice. Lean, PRCP-deficient (PRCPgt/gt) mice are constitutively hypertensive. Moreover, they are prothrombotic with shorter arterial thrombosis occlusion times after carotid artery photochemical- or ferric chloride-induced injury. The goal of this proposal is to determine if PRCP is a risk factor for hypertension and/or myocardial infarction (MI)/stroke with and without adjustment for body type, i.e. body mass index. The overall hypothesis of this proposal is that PRCP is a risk factor for hypertension and/or MI and stroke that are potentially mitigated by body mass index.
The specific aims of this proposal are:
Aim #1 : To determine if certain PRCP exon and intron SNPs are associated with hypertension status with and without adjustment for body mass index (BMI) status using DNA from individuals in the NIH/NHLBI PEACE and DASH-sodium studies. The subhypothesis for this aim is that PRCP SNPs that are associated with reduced PRCP function predicts hypertension status and this effect is mitigated by BMI status. We will also explore BMI stratified analyses of the association between PRCP SNPs and hypertension status.
Aim #2 : To determine if certain PRCP exon and intron SNPs are associated with a history of MI/stroke status with and without adjustment for hypertension and BMI status using DNA from individuals in the NIH/NHLBI PEACE study. The subhypothesis for this aim is that PRCP SNPs that are associated with reduced function increases risk for MI and/or stroke and these phenotypes are related to one's body mass index. We will also explore BMI stratified analyses of the association between PRCP SNPs and M/stroke status, adjusting for hypertension status. These investigations will be performed using SNPs that suggest predictable reduction in PRCP function. The selection of the exon SNPs for studies is based upon their structural location in PRCP that would have predictable alterations in the activity of the mature protein. Other SNPs are chosen because they are evolutionary conserved or in linkage disequilibrium with a functional SNP. The proposed investigations use NIH/NHLBI biorepository samples from two well-characterized cardiovascular studies (see letter enclosed);(1) the PEACE study which examined the addition of an ACE inhibitor in individuals with and without mild hypertension to ameliorate cardiovascular events and (2) the DASH-Sodium study that examined the influence of increasing dietary salt on hypertension in subjects with and without known hypertension. At their conclusion, these proposed investigations should show that certain polymorphisms in PRCP are associated with cardiovascular disease. Up-regulation of PRCP may be a target to protect individuals from cardiovascular disease as manifested by hypertension and arterial thrombosis as seen in stroke and MI.

Public Health Relevance

The overall goal of this proposal is to determine if PRCP is a risk factor for cardiovascular disease. We have recognized that PRCP deficient mice are hypertensive, have a lower threshold for arterial thrombosis, and are lean. In the proposed studies we aim to 1) determine if certain PRCP SNPs are associated with hypertension status with and without adjustment for body mass index (BMI) status using DNA from individuals in the NIH/NHLBI PEACE and DASH-sodium studies and 2) determine if certain PRCP SNPs are associated with a history of MI/stroke with and without adjustment for hypertension and BMI status using DNA from individuals in the NIH/NHLBI PEACE. At their conclusion, these investigations should show that certain polymorphisms in PRCP predict that it is a specific gene/protein that is associated with cardiovascular disease. Up-regulation of PRCP may protect individuals from cardiovascular disease as manifested by hypertension and arterial thrombosis as seen in MI/stroke.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Exploratory/Developmental Grants (R21)
Project #
1R21HL112666-01
Application #
8262208
Study Section
Special Emphasis Panel (ZHL1-CSR-P (F2))
Program Officer
Wagner, Elizabeth
Project Start
2012-04-01
Project End
2014-03-31
Budget Start
2012-04-01
Budget End
2013-03-31
Support Year
1
Fiscal Year
2012
Total Cost
$117,750
Indirect Cost
$42,750
Name
Case Western Reserve University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
077758407
City
Cleveland
State
OH
Country
United States
Zip Code
44106
Wang, J; Matafonov, A; Madkhali, H et al. (2014) Prolylcarboxypeptidase independently activates plasma prekallikrein (fletcher factor). Curr Mol Med 14:1173-85
Nayak, Lalitha; Shi, Hong; Atkins, G Brandon et al. (2014) The thromboprotective effect of bortezomib is dependent on the transcription factor Kruppel-like factor 2 (KLF2). Blood 123:3828-31
Schmaier, Alvin H (2014) Physiologic activities of the contact activation system. Thromb Res 133 Suppl 1:S41-4
Fang, Chao; Stavrou, Evi; Schmaier, Alec A et al. (2013) Angiotensin 1-7 and Mas decrease thrombosis in Bdkrb2-/- mice by increasing NO and prostacyclin to reduce platelet spreading and glycoprotein VI activation. Blood 121:3023-32
Adams, Gregory N; Stavrou, Evi X; Fang, Chao et al. (2013) Prolylcarboxypeptidase promotes angiogenesis and vascular repair. Blood 122:1522-31