Prolylcarboxypeptidase is a Risk Factor for Cardiovascular Disease

Summary

Principal Investigator: Alvin H Schmaier
Abstract: DESCRIPTION (provided by applicant): 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.
Funding Period: 2012-04-01 - 2014-10-31
more information: NIH RePORT

Top Publications

  1. pmc In vivo roles of factor XII
    Thomas Renne
    Department of Molecular Medicine and Surgery, Karolinska Institutet and University Hospital, Stockholm, Sweden
    Blood 120:4296-303. 2012
  2. pmc Angiotensin 1-7 and Mas decrease thrombosis in Bdkrb2-/- mice by increasing NO and prostacyclin to reduce platelet spreading and glycoprotein VI activation
    Chao Fang
    Hematology and Oncology Division, Department of Medicine, Case Western Reserve University, Cleveland, OH, USA
    Blood 121:3023-32. 2013
  3. pmc Prolylcarboxypeptidase promotes angiogenesis and vascular repair
    Gregory N Adams
    Department of Medicine, Hematology and Oncology Division, Case WesternReserve University and University Hospitals Case Medical Center, Cleveland, OH 44106, USA
    Blood 122:1522-31. 2013
  4. pmc Physiologic activities of the contact activation system
    Alvin H Schmaier
    Division of Hematology and Oncology, Case Western Reserve University, University Hospitals Case Medical Center, Cleveland, OH 44106, United States Electronic address
    Thromb Res 133:S41-4. 2014

Detail Information

Publications4

  1. pmc In vivo roles of factor XII
    Thomas Renne
    Department of Molecular Medicine and Surgery, Karolinska Institutet and University Hospital, Stockholm, Sweden
    Blood 120:4296-303. 2012
    ..The goal of this review is to summarize the in vivo functions of FXII, with special focus to its functions in thrombosis and vascular biology...
  2. pmc Angiotensin 1-7 and Mas decrease thrombosis in Bdkrb2-/- mice by increasing NO and prostacyclin to reduce platelet spreading and glycoprotein VI activation
    Chao Fang
    Hematology and Oncology Division, Department of Medicine, Case Western Reserve University, Cleveland, OH, USA
    Blood 121:3023-32. 2013
    ..In Bdkrb2(-/-), combined AT2R and Mas overexpression produce elevated plasma prostacyclin and NO leading to acquired platelet function defects and thrombosis delay...
  3. pmc Prolylcarboxypeptidase promotes angiogenesis and vascular repair
    Gregory N Adams
    Department of Medicine, Hematology and Oncology Division, Case WesternReserve University and University Hospitals Case Medical Center, Cleveland, OH 44106, USA
    Blood 122:1522-31. 2013
    ..PRCP regulates cell growth, angiogenesis, and the response to vascular injury. Combined with its known roles in blood pressure and thrombosis control, PRCP is positioned as a key regulator of vascular homeostasis. ..
  4. pmc Physiologic activities of the contact activation system
    Alvin H Schmaier
    Division of Hematology and Oncology, Case Western Reserve University, University Hospitals Case Medical Center, Cleveland, OH 44106, United States Electronic address
    Thromb Res 133:S41-4. 2014
    ..These observations suggest that thrombosis in mice of the CAS and KKS are mediated in part through the RAS and independent of reduced contact activation. ..

Research Grants30

  1. ETS-1 and Vascular and Renal Injury in Salt Sensitive Hypertension
    Edgar A Jaimes; Fiscal Year: 2013
    ..A better understanding of the mechanisms involved is critical in our efforts to develop novel strategies to prevent renal injury in hypertension, which would certainly result in improvements in morbidity and mortality in these patients. ..
  2. Dopamine and Angiotensin Receptor Interactions in Genetic Hypertension
    Robin A Felder; Fiscal Year: 2013
    ..abstract_text> ..
  3. Occult Small Vessel Cerebrovascular Disease in High Risk Families
    PAUL ALAN NYQUIST; Fiscal Year: 2013
    ..This study will be the first to examine small vessel disease in the brain and the heart in high risk family members who are notably susceptible to coronary heart disease and cerebrovascular disease. ..
  4. Women's Health Study: Continued Follow-up
    I Min Lee; Fiscal Year: 2013
    ..1 ..
  5. Signaling Processes Underlying Cardiovascular Function
    Jeffrey Robbins; Fiscal Year: 2013
    ..These projects are supported by 3 Cores: Core A: The Administrative Core;Core B: The Physiology Core and Core C: The Imaging-Cell Culture Core. (End of Abstract) ..
  6. Autocoids in Hypertension: Pathogenesis and End Organ Damage
    Oscar A Carretero; Fiscal Year: 2013
    ..Te PPG provides integration of our efforts, collaboration, sharing of ideas and expertise, thus accelerating acquisition of knowledge on the causes of hypertension and EOD. (End of Abstract) ..
  7. Ether Lipids, Elcosanoids, and Lung Cell Pathophysiology
    CHRISTINA CARROLL LESLIE; Fiscal Year: 2013
    ..By using multidisciplinary approaches, we will determine the structural identity of lipid mediators, the molecular mechanisms involved in their production and how they function to regulate lung responses. ..
  8. MOLECULAR &CELLULAR MECHANISMS IN TRANSFUSION MEDICINE
    Peter J Newman; Fiscal Year: 2013
    ..abstract_text> ..
  9. CARDIOVASCULAR DYNAMICS AND THEIR CONTROL
    John E Hall; Fiscal Year: 2013
    ..End of Abstract) ..