AKAP150-TRPV4 regulation of endothelial function in obesity
AKAP150-TRPV4 对肥胖内皮功能的调节
基本信息
- 批准号:10199007
- 负责人:
- 金额:$ 47.69万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2019
- 资助国家:美国
- 起止时间:2019-06-01 至 2024-05-31
- 项目状态:已结题
- 来源:
- 关键词:A kinase anchoring proteinAcetylcholineAddressAdultAffectArteriesAttenuatedBlood PressureBlood VesselsBradykininCardiovascular AbnormalitiesCardiovascular DiseasesCoupledDataDevelopmentDiseaseEndothelial CellsEndotheliumEventFoundationsG alpha q ProteinHeart DiseasesHigh Fat DietHypertensionImpairmentIndividualKnockout MiceKnowledgeMediatingMesenteric ArteriesMolecularMusNADPH OxidaseNerveObese MiceObesityPathologicPeptidesPeroxonitritePharmacologyPhysiologicalPlayProtein Kinase CProteinsReceptor SignalingRegulationResistanceRestRisk FactorsRoleSignal TransductionSmooth Muscle MyocytesStimulusStrokeTestingTherapeuticTherapeutic InterventionVanilloidVascular DiseasesVasodilationbaseblood pressure reductionblood pressure regulationcardiovascular risk factordesigndiet-induced obesityendothelial dysfunctionimprovedinhibitor/antagonistinsightnew therapeutic targetnovel therapeutic interventionreceptortool
项目摘要
Abstract.
More than one-third of U.S. adults suffer from obesity, which is also an underlying risk factor for cardiovascular
disorders including hypertension, stroke, and heart disease. It is, therefore, extremely important to understand
how obesity promotes the development of these disorders. Obesity-induced endothelial dysfunction plays a
crucial role in the development of cardiovascular abnormalities. In this application, we propose to address a
major gap in the knowledge about pathological mechanisms for obesity-induced endothelial dysfunction. In
resistance-sized arteries, endothelial Ca2+ signaling mechanisms regulate endothelium-dependent vasodilation.
However, endothelial Ca2+ signaling mechanisms remain unexplored in obesity. We recently showed that Ca2+
influx through individual TRPV4 (transient receptor potential vanilloid 4) channels promotes endothelium-
dependent vasodilation. Moreover, A kinase anchoring protein 150 (AKAP150), which can anchor protein kinase
A and protein kinase C, is a key regulator of TRPV4 channel activity in the endothelium. We postulate that
obesity-induced endothelial dysfunction reflects an impairment of AKAP150-TRPV4 channel regulation of
endothelial function. Our preliminary data demonstrate that TRPV4 channel function and endothelium-dependent
vasodilation are impaired, and blood pressure is elevated in high-fat diet-fed obese mice. Interestingly, TRPV4
channel function and TRPV4-mediated vasodilation were restored by peroxynitrite inhibitors, implicating a major
role for peroxynitrite in obesity-induced endothelial dysfunction. Peroxynitrite has been previously implicated in
vascular disorders, however, the molecular mechanisms for peroxynitrite-induced alteration of endothelial
function are not known. Our data support the concept that peroxynitrite targets endothelial AKAP150 to lower
TRPV4 channel activity. Therefore, we propose to test the hypothesis that peroxynitrite-induced impairment of
AKAP150-TRPV4 regulation of endothelial function contributes to obesity-induced hypertension. In Specific Aim
1, we will test the hypothesis that AKAP150-TRPV4 channel regulation of endothelial Ca2+ signaling is impaired
in obesity. We will also determine whether endothelium-specific deletion of AKAP150 or TRPV4 channels
elevates resting blood pressure. In Specific Aim 2, we will determine how peroxynitrite impairs AKAP150-TRPV4
regulation of endothelial function, and test the hypothesis that elevated peroxynitrite levels disrupt AKAP150-
TRPV4 regulation of endothelial function in obesity. These studies will identify new pathological mechanisms for
and novel therapeutic strategies against cardiovascular abnormalities in obesity.
抽象的。
超过三分之一的美国成年人患有肥胖症,这也是心血管疾病的潜在风险因素
包括高血压、中风和心脏病在内的疾病。因此,非常重要的是要理解
肥胖如何促进这些疾病的发展。肥胖引起的内皮功能障碍起着重要作用
在心血管异常的发展中起着至关重要的作用。在本应用程序中,我们建议解决一个
肥胖引起的内皮功能障碍的病理机制方面的主要知识空白。在……里面
阻力大小的动脉,内皮细胞钙信号机制调节内皮依赖的血管扩张。
然而,肥胖症患者血管内皮细胞钙信号转导机制尚不清楚。我们最近发现,钙离子
通过单独的TRPV4(瞬时受体电位香草素4)通道的流入促进内皮-
依赖性血管扩张。此外,AK锚定蛋白150(AKAP150)可以锚定蛋白激酶
A和蛋白激酶C是内皮细胞内TRPV4通道活性的关键调节因子。我们假定
肥胖诱导的内皮功能障碍反映了AKAP150-TRPV4通道调节的损害
内皮功能。我们的初步数据表明,TRPV4通道功能和内皮依赖性
高脂饮食喂养的肥胖小鼠的血管扩张功能受损,血压升高。有趣的是,TRPV4
过氧亚硝酸盐抑制剂可以恢复通道功能和TRPV4介导的血管扩张,这意味着主要的
过氧亚硝酸盐在肥胖诱导的内皮功能障碍中的作用。过氧亚硝酸盐此前曾被牵连到
然而,血管疾病,过氧亚硝酸盐诱导内皮细胞改变的分子机制
功能是未知的。我们的数据支持过氧亚硝酸靶向内皮细胞AKAP150降低
TRPV4通道活性。因此,我们建议检验过氧亚硝酸盐引起的脑细胞损伤的假设。
AKAP150-TRPV4对内皮功能的调节与肥胖引起的高血压有关。以特定的目标
1,我们将检验AKAP150-TRPV4通道对内皮细胞钙信号的调节受损的假设
在肥胖方面。我们还将确定AKAP150或TRPV4通道的内皮特异性缺失
提高静息血压。在特定目标2中,我们将确定过氧亚硝酸盐如何损害AKAP150-TRPV4
调节内皮功能,并检验过氧亚硝酸盐水平升高扰乱AKAP150的假设-
TRPV4对肥胖患者血管内皮功能的调节。这些研究将确定新的病理机制
以及针对肥胖症心血管异常的新治疗策略。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
数据更新时间:{{ journalArticles.updateTime }}
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
数据更新时间:{{ journalArticles.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ monograph.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ sciAawards.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ conferencePapers.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ patent.updateTime }}
Swapnil K. Sonkusare其他文献
Sa1162: 3D ARCHITECTURE OF THE INTESTINAL MICROVASCULATURE AND ITS ASSOCIATION TO THE ENTERIC NERVOUS SYSTEM AND INNATE IMMUNE CELLS
- DOI:
10.1016/s0016-5085(22)60789-3 - 发表时间:
2022-05-01 - 期刊:
- 影响因子:
- 作者:
JeongMin Natalie Kim;Glynn B. Reno;Caitlin P. Hodges;Tatiana M. Midkiff;Christina B. Bagnati;Connor A. Schroeder;John N. Pignataro;Sean M. Ward;David G. Binion;Swapnil K. Sonkusare;Anthony J. Bauer - 通讯作者:
Anthony J. Bauer
Endothelial Pannexin 1–TRPV4 channel signaling lowers pulmonary arterial pressure
内皮 Pannexin 1–TRPV4 通道信号传导降低肺动脉压
- DOI:
- 发表时间:
2021 - 期刊:
- 影响因子:0
- 作者:
Z. Daneva;Matteo Ottolini;Y. Chen;Eliška Klimentová;Soham A. Shah;R. Minshall;C. Seye;V. Laubach;B. Isakson;Swapnil K. Sonkusare - 通讯作者:
Swapnil K. Sonkusare
腸間膜血管内圧上昇に呼応した血管緊張におけるGDP/GTP交換因子p63RhoGEFの活性化
血管张力中 GDP/GTP 交换因子 p63RhoGEF 的激活响应肠系膜血管内压力增加
- DOI:
- 发表时间:
2019 - 期刊:
- 影响因子:0
- 作者:
Mykhaylo V. Artamonov;Swapnil K. Sonkusare;Miranda E. Good;Ko Momotani;Masumi Eto;Brant E. Isakson;Thu H. Le;Eric L. Cope;Zygmunt S. Derewenda;Urszula Derewenda;Avril V. Somlyo;坂井久美子 百渓江 - 通讯作者:
坂井久美子 百渓江
Expression of a β2 subunit mutant alters Ca currents in HL‐1 cells
β2 亚基突变体的表达改变 HL-1 细胞中的 Ca 电流
- DOI:
- 发表时间:
2006 - 期刊:
- 影响因子:0
- 作者:
Swapnil K. Sonkusare;J. Stimers;T. Grain;James DMarsh;S. Télémaque - 通讯作者:
S. Télémaque
Loss of local Ca2+ signaling networks in the endothelium in diet induced obesity
饮食引起的肥胖中内皮局部 Ca2 信号网络的丧失
- DOI:
- 发表时间:
2016 - 期刊:
- 影响因子:0
- 作者:
Kwang;Eric L. Cope;Corina Marziano;Swapnil K. Sonkusare - 通讯作者:
Swapnil K. Sonkusare
Swapnil K. Sonkusare的其他文献
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
{{ truncateString('Swapnil K. Sonkusare', 18)}}的其他基金
Novel Calcium Signaling Nanodomains in Vascular Smooth Muscle Cells
血管平滑肌细胞中的新型钙信号纳米结构域
- 批准号:
10744522 - 财政年份:2023
- 资助金额:
$ 47.69万 - 项目类别:
Impaired TRVP4-eNOS signaling in TM contributes to glaucoma
TM 中 TRVP4-eNOS 信号传导受损导致青光眼
- 批准号:
10503094 - 财政年份:2022
- 资助金额:
$ 47.69万 - 项目类别:
Impaired TRVP4-eNOS signaling in TM contributes to glaucoma
TM 中 TRVP4-eNOS 信号传导受损导致青光眼
- 批准号:
10880075 - 财政年份:2022
- 资助金额:
$ 47.69万 - 项目类别:
Cav-1.TRPV4 regulation of endothelial function in small pulmonary arteries
Cav-1.TRPV4对小肺动脉内皮功能的调节
- 批准号:
10163900 - 财政年份:2019
- 资助金额:
$ 47.69万 - 项目类别:
AKAP150-TRPV4 regulation of endothelial function in obesity
AKAP150-TRPV4 对肥胖内皮功能的调节
- 批准号:
10424433 - 财政年份:2019
- 资助金额:
$ 47.69万 - 项目类别:
Cav-1.TRPV4 regulation of endothelial function in small pulmonary arteries
Cav-1.TRPV4对小肺动脉内皮功能的调节
- 批准号:
9913574 - 财政年份:2019
- 资助金额:
$ 47.69万 - 项目类别:
AKAP150-TRPV4 regulation of endothelial function in obesity
AKAP150-TRPV4 对肥胖内皮功能的调节
- 批准号:
9925820 - 财政年份:2019
- 资助金额:
$ 47.69万 - 项目类别:
AKAP150-TRPV4 regulation of endothelial function in obesity
AKAP150-TRPV4 对肥胖内皮功能的调节
- 批准号:
10630829 - 财政年份:2019
- 资助金额:
$ 47.69万 - 项目类别:
Cav-1.TRPV4 regulation of endothelial function in small pulmonary arteries
Cav-1.TRPV4对小肺动脉内皮功能的调节
- 批准号:
10394403 - 财政年份:2019
- 资助金额:
$ 47.69万 - 项目类别:
Cav-1.TRPV4 regulation of endothelial function in small pulmonary arteries
Cav-1.TRPV4对小肺动脉内皮功能的调节
- 批准号:
10621152 - 财政年份:2019
- 资助金额:
$ 47.69万 - 项目类别:
相似海外基金
Spatiotemporal dynamics of acetylcholine activity in adaptive behaviors and response patterns
适应性行为和反应模式中乙酰胆碱活性的时空动态
- 批准号:
24K10485 - 财政年份:2024
- 资助金额:
$ 47.69万 - 项目类别:
Grant-in-Aid for Scientific Research (C)
Structural studies into human muscle nicotinic acetylcholine receptors
人体肌肉烟碱乙酰胆碱受体的结构研究
- 批准号:
MR/Y012623/1 - 财政年份:2024
- 资助金额:
$ 47.69万 - 项目类别:
Research Grant
CRCNS: Acetylcholine and state-dependent neural network reorganization
CRCNS:乙酰胆碱和状态依赖的神经网络重组
- 批准号:
10830050 - 财政年份:2023
- 资助金额:
$ 47.69万 - 项目类别:
Study on biological significance of acetylcholine and the content in food resources
乙酰胆碱的生物学意义及其在食物资源中的含量研究
- 批准号:
23K05090 - 财政年份:2023
- 资助金额:
$ 47.69万 - 项目类别:
Grant-in-Aid for Scientific Research (C)
alpha7 nicotinic acetylcholine receptor allosteric modulation and native structure
α7烟碱乙酰胆碱受体变构调节和天然结构
- 批准号:
10678472 - 财政年份:2023
- 资助金额:
$ 47.69万 - 项目类别:
Diurnal Variation in Acetylcholine Modulation of Dopamine Dynamics Following Chronic Cocaine Intake
慢性可卡因摄入后乙酰胆碱对多巴胺动力学调节的昼夜变化
- 批准号:
10679573 - 财政年份:2023
- 资助金额:
$ 47.69万 - 项目类别:
Striatal Regulation of Cortical Acetylcholine Release
纹状体对皮质乙酰胆碱释放的调节
- 批准号:
10549320 - 财政年份:2022
- 资助金额:
$ 47.69万 - 项目类别:
Differential Nicotinic Acetylcholine Receptor Modulation of Striatal Dopamine Release as a Mechanism Underlying Individual Differences in Drug Acquisition Rates
纹状体多巴胺释放的烟碱乙酰胆碱受体差异调节是药物获取率个体差异的机制
- 批准号:
10553611 - 财政年份:2022
- 资助金额:
$ 47.69万 - 项目类别:
Mechanisms of nicotinic acetylcholine receptor modulation of cocaine reward
烟碱乙酰胆碱受体调节可卡因奖赏的机制
- 批准号:
10672207 - 财政年份:2022
- 资助金额:
$ 47.69万 - 项目类别:
Structural basis of nicotinic acetylcholine receptor gating and toxin inhibition
烟碱乙酰胆碱受体门控和毒素抑制的结构基础
- 批准号:
10848770 - 财政年份:2022
- 资助金额:
$ 47.69万 - 项目类别: