Prolylcarboxypeptidase is a Risk Factor for Cardiovascular Disease

脯氨酰羧肽酶是心血管疾病的危险因素

• 批准号: 8448685
• 负责人: ALVIN H SCHMAIER
• 金额: $ 11.21万
• 依托单位: CASE WESTERN RESERVE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-04-01 至 2014-10-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8448685
• 关键词: Angiotensin II; Angiotensin-Converting Enzyme Inhibitors; Atherosclerosis; Biological Markers; Blood Coagulation Factor VII; Body mass index; Bradykinin; Cardiovascular Diseases; Cardiovascular system; Carotid Arteries; Cell surface; Cells; Chinese People; Chronic; DNA; Diabetes Mellitus; Diet; Disease; Endothelial Cells; Essential Hypertension; Event; Exons; Factor XIIa; Fibrinogen; Gene Proteins; Genes; Genetic Polymorphism; Goals; Hypertension; Hypothalamic structure; Individual; Injury; Introns; Investigation; Laboratories; Letters; Linkage Disequilibrium; Lipoprotein (a); Location; Metabolic syndrome; Metabolism; Mus; Myocardial Infarction; National Heart, Lung, and Blood Institute; Phenotype; Plasma; Plasma Kallikrein; Plasminogen Activator Inhibitor 1; Pre-Eclampsia; Prekallikrein; Prostate-Specific Antigen; Proteins; Reactive Oxygen Species; Recording of previous events; Resistance; Risk; Risk Factors; S100A8 gene; Sampling; Serine Protease; Sodium; Sodium Chloride; Somatotype; Stroke; Thrombosis; Time; Tissues; United States National Institutes of Health; Up-Regulation; Woman; base; biobank; ferric chloride; genome wide association study; hypercholesterolemia; hypertension treatment; lysosomal Pro-X carboxypeptidase; male; vascular inflammation

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.

描述（由申请人提供）：我们想确定脯氨酰羧肽酶（PRCP）是否是心血管疾病的危险因素。PRCP降解血管紧张素II（AngII）和缓激肽1-8。我们发现丝氨酸蛋白酶PRCP是一种不依赖于因子XIIa的细胞表面血浆前激肽释放酶激活剂. PRCP被预测为与原发性高血压相关的基因。在一项全基因组关联研究中，PRCP被确定为男性代谢综合征的危险因素。PRCP基因E112 D多态性与先兆子痫有关，尤其是在有慢性高血压病史的妇女中。此外，该多态性在汉族人群中的存在被证明与血管紧张素转换酶抑制剂治疗高血压的耐药相关。此外，我们表明PRCP将a-MSH 1 -13代谢为a-MSH 1 -12。在PRCP缺陷的小鼠中，该活性导致下丘脑中aMSH 1 -13代谢降低，从而允许过度刺激产生瘦小鼠的肥胖冲动。瘦的PRCP缺陷型（PRCPgt/gt）小鼠是体质性高血压。此外，它们是促血栓形成的，在颈动脉光化学或氯化铁诱导的损伤后具有较短的动脉血栓闭塞时间。本提案的目的是确定PRCP是否是高血压和/或心肌梗死（MI）/卒中的风险因素，并进行和不进行体型调整，即体重指数。该建议的总体假设是PRCP是高血压和/或MI和卒中的风险因素，可能通过体重指数减轻。本提案的具体目的是：目的#1：使用来自NIH/NHLBI PEACE和DASH-钠研究中个体的DNA，确定某些PRCP外显子和内含子SNP是否与高血压状态相关，是否调整了体重指数（BMI）状态。该目标的子假设是，与PRCP功能降低相关的PRCP SNP可预测高血压状态，并且该影响可通过BMI状态减轻。我们还将探讨BMI分层分析PRCP SNP和高血压状态之间的关联。目标二：使用NIH/NHLBI PEACE研究中个体的DNA，确定某些PRCP外显子和内含子SNP是否与MI/卒中状态病史相关，是否调整了高血压和BMI状态。该目的的子假设是与功能降低相关的PRCP SNP增加MI和/或中风的风险，并且这些表型与一个人的体重指数相关。我们还将探讨BMI分层分析PRCP SNP和M/卒中状态之间的关联，调整高血压状态。这些研究将使用提示PRCP功能可预测降低的SNP进行。用于研究的外显子SNP的选择是基于它们在PRCP中的结构位置，其将具有成熟蛋白活性的可预测的改变。选择其他SNP是因为它们是进化保守的或与功能性SNP连锁不平衡。拟议的研究使用来自两项充分表征的心血管研究的NIH/NHLBI生物储存库样本（见随附信件）;（1）PEACE研究，该研究检查了在患有和不患有轻度高血压的个体中添加ACE抑制剂以改善心血管事件;（2）DASH-钠研究，该研究检查了增加饮食盐对患有和不患有已知高血压的受试者中高血压的影响。在他们的结论中，这些拟议的研究应该表明PRCP的某些多态性与心血管疾病相关。PRCP的上调可能是保护个体免受心血管疾病的靶点，如中风和MI中所见的高血压和动脉血栓形成。