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Smooth Muscle Mineralocorticoid Receptor in Vascular Aging and Hypertension

血管老化和高血压中的平滑肌盐皮质激素受体

基本信息

批准号：
10396518
负责人：
Michael A HILL
金额：
$ 76.26万
依托单位：
TUFTS MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-08-05 至 2025-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10396518
关键词：
Adhesions Adult Age Aging Aldosterone Animal Model Aorta Atomic Force Microscopy Attenuated Automobile Driving Binding Biological Assay Blood Vessels Cardiovascular Diseases Cell Line Cytoskeletal Modeling Data Disease Outcome Down-Regulation EZH2 gene Elderly Epigenetic Process Event Female Fibrosis Funding Future Genes Genetic Genetic Transcription Goals Heart Diseases Heart failure Histology Histones Human Hydrogen Peroxide Hypertension Impaired cognition In Vitro Integrins Knockout Mice Lead Life MMP2 gene Mass Spectrum Analysis Measurement Medical Messenger RNA Methylation Methyltransferase Mineralocorticoid Receptor Modeling Molecular Biology Mus Myocardial Infarction Organ Outcome Pattern Pharmacology Process Proteomics Pulse Pressure Quantitative Reverse Transcriptase PCR Receptor Up-Regulation Reporter Risk Factors Sex Differences Smooth Muscle Smooth Muscle Myocytes Sodium Chloride Stroke Structure Testing Therapeutic Time Tissues Transcriptional Activation Vascular Smooth Muscle Woman adverse outcome aged aging population antagonist arterial stiffness base cardiovascular disorder risk cardiovascular risk factor chromatin immunoprecipitation connective tissue growth factor heart disease risk hypoxia inducible factor 1 innovation kidney dysfunction loss of function male men novel precision medicine prevent promoter receptor receptor expression recruit sex sexual dimorphism transcription factor

项目摘要

Aging is universal and the most potent risk factor for cardiovascular disease (CVD). Aortic stiffness increases with age in both sexes and predicts CVD risk. Stiffening of the aorta raises central pulse pressure to contribute to hypertension, heart attack and stroke and promotes small vessel remodeling that damages end organs inducing heart failure, renal dysfunction, and cognitive decline. Thus, understanding aging vascular stiffness mechanisms is a pressing unmet medical need. We recently discovered that inhibition of the aldosterone- binding mineralocorticoid receptor (MR) or smooth muscle cell (SMC)-specific deletion of MR (SMC-MR-KO) protects male mice from vascular stiffness with aging and now propose to explore mechanism(s). Women develop vascular stiffness later in life, faster, and with significantly worse CVD outcomes than men. New data reveals a similar pattern of later onset vascular stiffness in aging female mice that correlates with the timing of increased aortic SMC-MR expression. SMC-MR deletion protects from vascular stiffening in both sexes by sexually dimorphic mechanisms; SMC-MR contributes to vessel fibrosis in aging males and to intrinsic SMC stiffness (by atomic force microscopy (AFM)) in both sexes. We show for the first time that MR protein increases with age in primary human aortic SMCs (HASMC) from males and females which may be driven by induction of the HIF1a transcription factor. Additional data from male mouse aortas reveals: (1) Decreased expression with age of fibrosis genes and integrin receptors specifically in SMC-MR-KO mice; (2) Decreased histone H3K27 methylation (H3K27me) with aging that is attenuated in SMC-MR-KO mice; (3) Decreased expression of the H3K27 methyltransferase EZH2 with age with enrichment of H3K27ac, a transcriptional activation mark, at promoters of fibrosis genes only in MR-intact mice. Analogous to the mice, aged male HASMC had decreased EZH2 and H3K27me and increased stiffness genes, and these changes are reversed by MR antagonism. Based on these data, we propose to test the hypothesis that: rising MR in aging SMC promotes stiffness by suppression of EZH2 leading to decreased H3K27me and recruitment of MR and it's co- activator CBP to increase H3K27ac and transcription of stiffness genes. SA1 determines mechanisms for increased MR expression in aging SMCs. SA2 investigates MR as an epigenetic regulator of stiffness genes in HASMCs in vitro. SA3 explores MR as an epigenetic regulator of vascular stiffness in aging mice. All studies directly compare male and female HASMCs or mice with gain- and loss-of-function genetic and pharmacologic approaches to target MR, EZH2, and CBP. The proposal uses innovative animal models and state-of-the-art approaches to explore a novel epigenetic mechanism driving aging vascular stiffness and tests sex-specific mechanisms by which SMC-MR contributes. The long-term goal is to determine the therapeutic potential for antagonism of MR or its downstream mechanisms as sex-specific precision medicine strategies to mitigate aging-induced vascular stiffness and the myriad of adverse consequences in our rapidly aging population.

老龄化是普遍的，也是心血管疾病（CVD）最有力的危险因素。主动脉僵硬度增加与年龄相关，并预测CVD风险。主动脉硬化导致中心脉压升高高血压、心脏病发作和中风，并促进小血管重塑，损害终末器官导致心力衰竭、肾功能障碍和认知能力下降。因此，了解老化血管硬度机制是一个迫切的未满足的医疗需求。我们最近发现抑制醛固酮- 结合盐皮质激素受体（MR）或平滑肌细胞（SMC）特异性MR缺失（SMC-MR-KO）保护雄性小鼠免受血管硬化的影响，现在正在研究其机制。妇女与男性相比，老年人在生命后期更快地发展血管僵硬，并且CVD结果显著更差。新数据揭示了衰老雌性小鼠中晚发性血管僵硬的类似模式，其与以下时间相关：主动脉SMC-MR表达增加。SMC-MR缺失通过以下方式保护两种性别的血管硬化：性二态机制; SMC-MR有助于老年男性的血管纤维化和内在SMC 硬度（原子力显微镜（AFM））在两种性别。我们首次发现MR蛋白男性和女性的原代人主动脉SMC（HASMC）随着年龄的增长而增加，这可能是由以下因素驱动的 HIF 1a转录因子的诱导。来自雄性小鼠睾丸的其他数据显示：（1）在SMC-MR-KO小鼠中特异性的纤维化基因和整联蛋白受体随年龄的表达;（2）降低组蛋白H3 K27甲基化（H3 K27 me）随着年龄的增长而减弱，在SMC-MR-KO小鼠中;（3）降低 H3 K27甲基转移酶EZH 2的表达随着年龄的增长而富集H3 K27 ac，这是一种转录因子。激活标记，仅在MR完整小鼠中的纤维化基因的启动子处。与老鼠相似，老年雄性 HASMC具有减少的EZH 2和H3 K27 me和增加的刚度基因，并且这些变化被逆转 MR拮抗作用。基于这些数据，我们提出了以下假设：在老化SMC中，通过抑制EZH 2促进僵硬，导致H3 K27 me减少和MR的募集，激活剂CBP增加H3 K27 ac和刚度基因的转录。SA 1确定机制增加衰老SMC中的MR表达。SA 2研究了MR作为强直基因的表观遗传调节因子，体外HASMCs。SA 3探讨了MR作为衰老小鼠血管硬度的表观遗传调节因子。所有研究直接比较雄性和雌性HASMC或小鼠的功能获得和丧失遗传和药理学针对MR、EZH 2和CBP的方法。该提案使用了创新的动物模型和最先进的探索一种新的表观遗传机制驱动衰老血管硬度的方法，并测试性别特异性 SMC-MR的作用机制。长期目标是确定治疗潜力，拮抗MR或其下游机制作为性别特异性精准医学策略，在我们快速老龄化的人群中，老化引起的血管僵硬和无数的不良后果。

项目成果

期刊论文数量（34）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Acute effect of mineralocorticoid receptor antagonism on vascular function in healthy older adults.

盐皮质激素受体拮抗剂对健康老年人血管功能的急性影响。

DOI：
10.1016/j.exger.2015.11.017
发表时间：
2016
期刊：
Experimental gerontology
影响因子：
3.9
作者：
Hwang,Moon-Hyon;Yoo,Jeung-Ki;Luttrell,Meredith;Kim,Han-Kyul;Meade,ThomasH;English,Mark;Talcott,Susanne;Jaffe,IrisZ;Christou,DemetraD
通讯作者：
Christou,DemetraD

Circulating multimarker profile of patients with symptomatic heart failure supports enhanced fibrotic degradation and decreased angiogenesis.

DOI：
10.3109/1354750x.2015.1118539
发表时间：
2016
期刊：
Biomarkers : biochemical indicators of exposure, response, and susceptibility to chemicals
影响因子：
0
作者：
Morine KJ;Paruchuri V;Qiao X;Mohammad N;Mcgraw A;Yunis A;Jaffe I;Kapur NK
通讯作者：
Kapur NK

Vascular mineralocorticoid receptor regulates microRNA-155 to promote vasoconstriction and rising blood pressure with aging.

DOI：
10.1172/jci.insight.88942
发表时间：
2016-09-08
期刊：
JCI insight
影响因子：
8
作者：
DuPont JJ;McCurley A;Davel AP;McCarthy J;Bender SB;Hong K;Yang Y;Yoo JK;Aronovitz M;Baur WE;Christou DD;Hill MA;Jaffe IZ
通讯作者：
Jaffe IZ

30 YEARS OF THE MINERALOCORTICOID RECEPTOR: The role of the mineralocorticoid receptor in the vasculature.