Mineralocorticoid receptor mediates vascular stiffness via dysregulated immunity in perivascular adipose tissue

盐皮质激素受体通过血管周围脂肪组织免疫失调介导血管僵硬度

基本信息

批准号：
10078620
负责人：
Guido Lastra
金额：
$ 16.77万
依托单位：
UNIVERSITY OF MISSOURI-COLUMBIA
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-01-01 至 2022-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10078620
关键词：
Address Adipose tissue Adoptive Transfer Affect Aldosterone Anti-Inflammatory Agents Atomic Force Microscopy Bioavailable Biological Markers Blood Vessels Cardiovascular Diseases Cells Collagen Consumption Cultured Cells Data Development Development Plans Diet Dose Elastin Endothelial Cells Endothelium Event Exposure to Extracellular Matrix Proteins FOXP3 gene Fatty acid glycerol esters Female Fibrosis Fructose Goals Gonadal Steroid Hormones Immunity Impairment Inflammation Inflammatory Infrastructure Infusion procedures Institution Insulin Resistance Intervention Knock-out Knockout Mice Knowledge Laboratories Lead Measurement Measures Mediating Mentors Mineralocorticoid Receptor Modeling Mus Myelogenous Myeloid Cell Activation Myeloid Cells NADPH Oxidase Nitric Oxide Obesity Outcome Oxidative Stress Pathogenesis Pericytes Physiologic pulse Play Premenopause Production Reactive Oxygen Species Receptor Activation Receptor Signaling Regulatory T-Lymphocyte Research Research Personnel Resources Role Smooth Muscle Myocytes Societies T-Lymphocyte Testing Tissues Training Vascular Diseases Vascular Endothelial Cell Vascular Smooth Muscle Vascular remodeling Vasodilation Vasomotor Woman Work blood damage career development cohort crosslink endothelial dysfunction experimental study feeding heart disease risk in vivo inflammatory marker macrophage male men novel prevent response sugar transglutaminase 2 translational study vascular injury western diet

项目摘要

Project summary My research is focused on the interactions between mineralocorticoid receptor (MR) signaling in perivascular adipose tissue (PVAT), dysregulation of immunity and vascular dysfunction in the setting of high-fat high- fructose diet (Western Diet [WD]). WD leads to insulin resistance. Importantly, insulin resistance leads to aggressive cardiovascular disease in females. I hypothesize that in females, WD-induced insulin resistance results in loss of T regulatory (Treg) function leading to macrophage MR activation and subsequent M1 polarization in PVAT. Further, I hypothesize that these events increase vascular stiffness via activation of Tissue transglutaminase-2 (TG2), in part, through oxidative stress and decreased bioavailable nitric oxide (NO). To test my hypothesis, specific Aim 1 is to determine the effect of MR activation in PVAT macrophages on the pathogenesis of vascular stiffness as it relates to impaired Treg function and M1 macrophage polarization. Myeloid-specific MR knockout (MyMRKO) male and female mice will be treated with a WD or aldosterone and we will measure aortic stiffness. In PVAT, we will measure macrophage polarization and inflammation. We will measure cellular stiffness in primary endothelial cells (EC) and vascular smooth muscle cells (VSMC) cultured in PVAT-conditioned media from each cohort. In Specific Aim 2, we will determine the role of Tregs on PVAT macrophage polarization and aortic stiffness. In this set of experiments, we will use adoptive Treg transfer from male and female C57Bl/6J mice fed a normal diet to the mice treated with WD or slow pressor doses of aldosterone. We will measure macrophage polarization, inflammation and aortic stiffness, along with EC/VSMC stiffness measurement in PVAT-conditioned media. I have assembled a team of mentors and collaborators that will guide me throughout this project and promote my transition as an independent researcher. My career development plan has an initial training period (years 1-3) in which I will complete the proposed work, and a transitional period (years 4-5) during which I will focus on an R01 proposal. My mentoring team has the necessary infrastructure, expertise and resources and my institution will provide the necessary support to enable me successfully achieve my goals. My intermediate goal is to successfully complete the work I propose. My ultimate goal is to establish a distinct line of work addressing the mechanisms by which MR activation and dysregulated immunity lead to vascular disease.

项目概要我的研究重点是血管周围盐皮质激素受体 (MR) 信号传导之间的相互作用高脂高脂环境下的脂肪组织（PVAT）、免疫失调和血管功能障碍果糖饮食（西方饮食[WD]）。 WD 会导致胰岛素抵抗。重要的是，胰岛素抵抗会导致女性的侵袭性心血管疾病。我假设在女性中，WD 诱导的胰岛素抵抗导致 T 调节 (Treg) 功能丧失，从而导致巨噬细胞 MR 激活和随后的 M1 PVAT 中的极化。此外，我假设这些事件通过激活组织转谷氨酰胺酶 2 (TG2) 部分通过氧化应激和生物可利用一氧化氮减少（不）。为了检验我的假设，具体目标 1 是确定 MR 激活对 PVAT 巨噬细胞的影响血管僵硬的发病机制，因为它与 Treg 功能和 M1 巨噬细胞受损有关极化。骨髓特异性 MR 敲除 (MyMRKO) 雄性和雌性小鼠将接受 WD 或醛固酮，我们将测量主动脉僵硬度。在 PVAT 中，我们将测量巨噬细胞极化并炎。我们将测量原代内皮细胞 (EC) 和血管平滑肌的细胞硬度来自每个队列的细胞（VSMC）在 PVAT 条件培养基中培养。在具体目标 2 中，我们将确定 Tregs 对 PVAT 巨噬细胞极化和主动脉僵硬度的作用。在这组实验中，我们将使用将正常饮食的雄性和雌性 C57Bl/6J 小鼠的 Treg 细胞过继转移至接受 WD 或缓慢加压醛固酮剂量。我们将测量巨噬细胞极化、炎症和主动脉刚度，以及 PVAT 条件介质中的 EC/VSMC 刚度测量。我已经组建了一个团队导师和合作者将在整个项目中指导我并促进我作为一名独立研究员。我的职业发展计划有一个初始培训期（第 1-3 年），在此期间我将完成拟议的工作，以及一个过渡期（第 4-5 年），在此期间我将重点关注 R01 提案。我的指导团队拥有必要的基础设施、专业知识和资源，我的机构将提供必要的支持使我能够成功实现我的目标。我的中期目标是成功完成我提议的工作。我的最终目标是建立一条独特的工作线来解决这些机制 MR 激活和免疫失调导致血管疾病。

项目成果

期刊论文数量（9）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Xanthine oxidase inhibition protects against Western diet-induced aortic stiffness and impaired vasorelaxation in female mice.

DOI：
10.1152/ajpregu.00483.2016
发表时间：
2017-08
期刊：
American journal of physiology. Regulatory, integrative and comparative physiology
影响因子：
0
作者：
G. Lastra;C. Manrique;Guanghong Jia;A. Aroor;M. Hayden;Brady J Barron;B. Niles;J. Padilla;J. Sowers
通讯作者：
G. Lastra;C. Manrique;Guanghong Jia;A. Aroor;M. Hayden;Brady J Barron;B. Niles;J. Padilla;J. Sowers

Endothelial sodium channel activation promotes cardiac stiffness and diastolic dysfunction in Western diet fed female mice.

DOI：
10.1016/j.metabol.2020.154223
发表时间：
2020-08
期刊：
Metabolism: clinical and experimental
影响因子：
0
作者：
Sowers JR;Habibi J;Jia G;Bostick B;Manrique-Acevedo C;Lastra G;Yang Y;Chen D;Sun Z;Domeier TL;Durante W;Whaley-Connell AT;Hill MA;Jaisser F;DeMarco VG;Aroor AR
通讯作者：
Aroor AR

Mineralocorticoids and Cardiovascular Disease in Females with Insulin Resistance and Obesity.

DOI：
10.1007/s11906-018-0887-6
发表时间：
2018-08-14
期刊：
Current hypertension reports
影响因子：
5.6
作者：
Nayyar M;Lastra G;Acevedo CM
通讯作者：
Acevedo CM

Mineralocorticoid Receptor in Myeloid Cells Mediates Angiotensin II-Induced Vascular Dysfunction in Female Mice.

DOI：
10.3389/fphys.2021.588358
发表时间：
2021
期刊：
Frontiers in physiology
影响因子：
4
作者：
Manrique-Acevedo C;Padilla J;Naz H;Woodford ML;Ghiarone T;Aroor AR;Hulse JL;Cabral-Amador FJ;Martinez-Diaz V;Hans CP;Whaley-Connell A;Martinez-Lemus LA;Lastra G
通讯作者：
Lastra G

Sexual dimorphism in obesity-associated endothelial ENaC activity and stiffening in mice.

DOI：
10.1210/en.2019-00483
发表时间：
2019-10
期刊：
Endocrinology
影响因子：
4.8
作者：
J. Padilla;Makenzie L. Woodford;Guido Lastra-Gonzalez;Vanesa Martinez-Diaz;S. Fujie;Yan Yang;
通讯作者：
J. Padilla;Makenzie L. Woodford;Guido Lastra-Gonzalez;Vanesa Martinez-Diaz;S. Fujie;Yan Yang;