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Vascular Smooth Muscle Function in Pulmonary Hypertension

肺动脉高压中的血管平滑肌功能

基本信息

批准号：
10402413
负责人：
Nikki L Jernigan
金额：
$ 37.88万
依托单位：
UNIVERSITY OF NEW MEXICO HEALTH SCIS CTR
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-02-01 至 2025-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10402413
关键词：
ASIC channel Acidosis Animals Apoptosis Apoptotic Bioenergetics Blood Vessels Cell Death Cell membrane Cells Cessation of life Chronic Complex Data Degenerative Disorder Deoxyglucose Development Disease Event Future Genetic Glycolysis Glycolysis Inhibition Hypoxia Inner mitochondrial membrane Ion Pumps Life Lung Malignant Neoplasms Mediating Membrane Membrane Potentials Membrane Proteins Metabolic Metabolic dysfunction Metabolism Mitochondria Molecular Morphology Muscle Muscle function Muscular Atrophy Outcome Oxidative Phosphorylation Pathogenicity Pharmacology Phenotype Play Pulmonary Hypertension Pulmonary Vascular Resistance Regulation Resistance Respiration Right Ventricular Hypertrophy Role Signal Transduction Smooth Muscle Myocytes Stimulus Testing Therapeutic Up-Regulation Vascular Proliferation Vascular Smooth Muscle Vascular resistance Warburg Effect aerobic glycolysis cell type experimental study extracellular genetic approach glucose uptake glycosylation mitochondrial dysfunction mitochondrial membrane mitochondrial metabolism novel therapeutic intervention novel therapeutics pulmonary vascular remodeling right ventricular failure trafficking vasoconstriction

项目摘要

PROJECT SUMMARY/ABSTRACT Pulmonary hypertension (pHTN) is a complex, progressive condition leading to increased pulmonary vascular resistance, right heart failure and ultimately death. Although pHTN arises from a variety of genetic and pathogenic causes, it is widely recognized that structural alterations in the vascular wall contribute to all forms of pHTN. A chronic shift in cellular metabolism from mitochondrial oxidative phosphorylation to aerobic glycolysis underlies the hyperproliferative and anti-apoptotic phenotype within the pulmonary vasculature. These metabolic derangements are accompanied by H+ extrusion creating an alkalotic intracellular pH while acidifying the extracellular microenvironment; conditions that activate the H+-gated acid sensing ion channel 1 (ASIC1). ASIC1 conducts both Na+ and Ca2+ and activation leads to membrane depolarization and variety of intracellular Ca2+ signaling events. Our previous studies show ASIC1 contributes to the development of pHTN and is associated with greater localization of ASIC1 at the plasma membrane of pulmonary arterial smooth muscle cells (PASMC) and loss of ASIC1 in the mitochondria. Neither the role of ASIC1 in the mitochondria, nor the contribution of ASIC1 to metabolic-mitochondrial dysfunction are known. Therefore, the overall objective of this application is to determine the contribution of ASIC1 to the metabolic derangements that promote a proliferative, apoptosis-resistant phenotype associated with pHTN. We will test the central hypothesis that ASIC1 contributes to metabolic dysfunction in pHTN as a result of altered subcellular localization and regulation of PASMC plasma membrane and mitochondrial membrane potential with the following two specific aims: 1) Determine the impact of altered cellular metabolism on ASIC1 localization and activation. We will test the working hypothesis that enhanced glucose uptake and subsequent acidification of the extracellular microenvironment in pHTN leads to increased localization/activation of ASIC1 at the plasma membrane, plasma membrane depolarization, and proliferation. 2) Examine the functional role of mitochondrial ASIC1 (mtASIC1) in regulation of mitochondrial membrane potential (m) and apoptosis. We will test the working hypothesis that mtASIC1 contributes to mitochondrial m depolarization and apoptosis. Furthermore, loss of mtASIC1 in pHTN leads to mitochondrial m hyperpolarization and apoptosis-resistance. Successful completion of the proposed studies is expected to define a role for ASIC1 in regulating mitochondrial dynamics and metabolic dysfunction. These outcomes will enable a fundamental understanding of ASIC1 in various proliferative and degenerative diseases, which will permit future studies to evaluate the therapeutic potential of ASIC1.

项目总结/摘要肺动脉高压（pHTN）是一种复杂的、进行性的疾病，导致肺血管扩张和肺动脉高压。抵抗右心衰竭最终死亡尽管pHTN源于多种遗传和尽管血管壁的结构改变是致病原因的一部分，但人们普遍认为，血管壁的结构改变有助于所有形式的致病原因，的pHTN。细胞代谢从线粒体氧化磷酸化到有氧代谢的慢性转变糖酵解是肺脉管系统内过度增殖和抗凋亡表型的基础。这些代谢紊乱伴随着H+挤出，产生了细胞内的pH值，酸化细胞外微环境;激活H+门控酸敏感离子通道1的条件（ASIC 1）。ASIC 1传导Na+和Ca 2+，并且激活导致膜去极化和多种细胞因子。细胞内Ca 2+信号传导事件。我们前期的研究表明ASIC 1参与了pHTN的形成并且与ASIC 1在肺动脉平滑肌细胞质膜上的更大定位相关。肌细胞（PASMC）和线粒体中ASIC 1的丢失。ASIC 1在线粒体中的作用， ASIC 1对代谢线粒体功能障碍的作用是已知的。因此，总体目标本申请的目的是确定ASIC 1对促进代谢紊乱的贡献。与pHTN相关的增殖性、抗肿瘤表型。我们将检验中心假设， ASIC 1作为改变的亚细胞定位的结果导致pHTN中的代谢功能障碍，调节PASMC质膜和线粒体膜电位与以下两个具体目的：1）确定改变的细胞代谢对ASIC 1定位和激活的影响。我们将测试工作假设，即增强葡萄糖摄取和随后的酸化， pHTN中的细胞外微环境导致ASIC 1在血浆中的定位/活化增加膜、质膜去极化和增殖。2)审查的职能作用线粒体ASIC 1（mtASIC 1）在调节线粒体膜电位和细胞凋亡中的作用。我们将检验mtASIC 1促进线粒体膜去极化的工作假设，凋亡此外，pHTN中mtASIC 1的缺失导致线粒体膜超极化，抗衰老拟议研究的成功完成预计将确定ASIC 1在以下方面的作用：调节线粒体动力学和代谢功能障碍。这些成果将使一个基本的了解ASIC 1在各种增殖性和退行性疾病中的作用，这将使未来的研究能够评估ASIC 1的治疗潜力。

项目成果

期刊论文数量（12）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Redox Regulation of Ion Channels and Receptors in Pulmonary Hypertension.

DOI：
10.1089/ars.2018.7699
发表时间：
2019-09
期刊：
Antioxidants & redox signaling
影响因子：
6.6
作者：
Laura Weise-Cross;T. Resta;Nikki L. Jernigan
通讯作者：
Laura Weise-Cross;T. Resta;Nikki L. Jernigan

Pulmonary Arterial Smooth Muscle Cell Monocarboxylate Transporter 1/4 Contributes to Extracellular Acidosis following Chronic Hypoxia-induced Pulmonary Hypertension.

肺动脉平滑肌细胞单羧酸转运蛋白 1/4 导致慢性缺氧引起的肺动脉高压后出现细胞外酸中毒。

DOI：
发表时间：
2022
期刊：
FASEB journal : official publication of the Federation of American Societies for Experimental Biology
影响因子：
0
作者：
Tuineau,MeganN;Herbert,LindsayM;Resta,ThomasC;Jernigan,NikkiL
通讯作者：
Jernigan,NikkiL

Acid-sensing ion channel 1 contributes to pulmonary arterial smooth muscle cell depolarization following hypoxic pulmonary hypertension.

DOI：
10.1113/jp282231
发表时间：
2021-11
期刊：
The Journal of physiology
影响因子：
0
作者：
Jernigan NL;Naik JS;Resta TC
通讯作者：
Resta TC

Vasoconstrictor Mechanisms in Chronic Hypoxia-Induced Pulmonary Hypertension: Role of Oxidant Signaling.

DOI：
10.3390/antiox9100999
发表时间：
2020-10-15
期刊：
Antioxidants (Basel, Switzerland)
影响因子：
0
作者：
Yan S;Resta TC;Jernigan NL
通讯作者：
Jernigan NL

Inducible Smooth Muscle-Specific Knockout of Acid Sensing Ion Channel 1 Protects Against Pulmonary Hypertension.

诱导性平滑肌特异性敲除酸敏感离子通道 1 可预防肺动脉高压。

DOI：
发表时间：
2022
期刊：
FASEB journal : official publication of the Federation of American Societies for Experimental Biology
影响因子：
0
作者：
Garcia,SelinaM;Yellowhair,TracylynR;Ahmadian,Rosstin;Herbert,LindsayM;GonzalezBosc,LauraV;Resta,ThomasC;Jernigan,NikkiL
通讯作者：
Jernigan,NikkiL