Internalized β2-Adrenergic Receptors Oppose PLC-Dependent Hypertrophic Signaling.

IF 16.5 1区 医学 Q1 CARDIAC & CARDIOVASCULAR SYSTEMS Circulation research Pub Date : 2024-07-05 Epub Date: 2024-05-30 DOI:10.1161/CIRCRESAHA.123.323201
Wenhui Wei, Alan V Smrcka
{"title":"Internalized β2-Adrenergic Receptors Oppose PLC-Dependent Hypertrophic Signaling.","authors":"Wenhui Wei, Alan V Smrcka","doi":"10.1161/CIRCRESAHA.123.323201","DOIUrl":null,"url":null,"abstract":"<p><strong>Background: </strong>Chronically elevated neurohumoral drive, and particularly elevated adrenergic tone leading to β-adrenergic receptor (β-AR) overstimulation in cardiac myocytes, is a key mechanism involved in the progression of heart failure. β1-AR (β1-adrenergic receptor) and β2-ARs (β2-adrenergic receptor) are the 2 major subtypes of β-ARs present in the human heart; however, they elicit different or even opposite effects on cardiac function and hypertrophy. For example, chronic activation of β1-ARs drives detrimental cardiac remodeling while β2-AR signaling is protective. The underlying molecular mechanisms for cardiac protection through β2-ARs remain unclear.</p><p><strong>Methods: </strong>β2-AR signaling mechanisms were studied in isolated neonatal rat ventricular myocytes and adult mouse ventricular myocytes using live cell imaging and Western blotting methods. Isolated myocytes and mice were used to examine the roles of β2-AR signaling mechanisms in the regulation of cardiac hypertrophy.</p><p><strong>Results: </strong>Here, we show that β2-AR activation protects against hypertrophy through inhibition of phospholipaseCε signaling at the Golgi apparatus. The mechanism for β2-AR-mediated phospholipase C inhibition requires internalization of β2-AR, activation of Gi and Gβγ subunit signaling at endosome and ERK (extracellular regulated kinase) activation. This pathway inhibits both angiotensin II and Golgi-β1-AR-mediated stimulation of phosphoinositide hydrolysis at the Golgi apparatus ultimately resulting in decreased PKD (protein kinase D) and histone deacetylase 5 phosphorylation and protection against cardiac hypertrophy.</p><p><strong>Conclusions: </strong>This reveals a mechanism for β2-AR antagonism of the phospholipase Cε pathway that may contribute to the known protective effects of β2-AR signaling on the development of heart failure.</p>","PeriodicalId":10147,"journal":{"name":"Circulation research","volume":null,"pages":null},"PeriodicalIF":16.5000,"publicationDate":"2024-07-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11223973/pdf/","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Circulation research","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1161/CIRCRESAHA.123.323201","RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"2024/5/30 0:00:00","PubModel":"Epub","JCR":"Q1","JCRName":"CARDIAC & CARDIOVASCULAR SYSTEMS","Score":null,"Total":0}
引用次数: 0

Abstract

Background: Chronically elevated neurohumoral drive, and particularly elevated adrenergic tone leading to β-adrenergic receptor (β-AR) overstimulation in cardiac myocytes, is a key mechanism involved in the progression of heart failure. β1-AR (β1-adrenergic receptor) and β2-ARs (β2-adrenergic receptor) are the 2 major subtypes of β-ARs present in the human heart; however, they elicit different or even opposite effects on cardiac function and hypertrophy. For example, chronic activation of β1-ARs drives detrimental cardiac remodeling while β2-AR signaling is protective. The underlying molecular mechanisms for cardiac protection through β2-ARs remain unclear.

Methods: β2-AR signaling mechanisms were studied in isolated neonatal rat ventricular myocytes and adult mouse ventricular myocytes using live cell imaging and Western blotting methods. Isolated myocytes and mice were used to examine the roles of β2-AR signaling mechanisms in the regulation of cardiac hypertrophy.

Results: Here, we show that β2-AR activation protects against hypertrophy through inhibition of phospholipaseCε signaling at the Golgi apparatus. The mechanism for β2-AR-mediated phospholipase C inhibition requires internalization of β2-AR, activation of Gi and Gβγ subunit signaling at endosome and ERK (extracellular regulated kinase) activation. This pathway inhibits both angiotensin II and Golgi-β1-AR-mediated stimulation of phosphoinositide hydrolysis at the Golgi apparatus ultimately resulting in decreased PKD (protein kinase D) and histone deacetylase 5 phosphorylation and protection against cardiac hypertrophy.

Conclusions: This reveals a mechanism for β2-AR antagonism of the phospholipase Cε pathway that may contribute to the known protective effects of β2-AR signaling on the development of heart failure.

查看原文
分享 分享
微信好友 朋友圈 QQ好友 复制链接
本刊更多论文
内化的β2-肾上腺素能受体反对PLC依赖性肥大信号传导
背景:神经体液驱动力的长期升高,特别是肾上腺素能张力的升高导致心肌细胞中的β-肾上腺素能受体(β-AR)过度刺激,是心力衰竭进展的一个关键机制。β1-AR(β1-肾上腺素能受体)和β2-AR(β2-肾上腺素能受体)是人体心脏中存在的两种主要的β-AR亚型,但它们对心脏功能和肥大的影响不同,甚至相反。例如,β1-ARs 的慢性激活会导致有害的心脏重塑,而 β2-AR 信号转导则具有保护作用。方法:采用活细胞成像和 Western 印迹方法,在离体新生大鼠心室肌细胞和成年小鼠心室肌细胞中研究了β2-AR 信号传导机制。利用离体心肌细胞和小鼠研究了这些信号传导方法在调控心脏肥大中的作用:结果:我们在这里发现,β2-AR 激活通过抑制高尔基体上的磷脂酶 Cε 信号传导来防止肥大。β2-AR介导的磷脂酶C抑制机制需要β2-AR的内化、内质体中Gi和Gβγ亚基信号的激活以及ERK(细胞外调节激酶)的激活。这一途径可抑制血管紧张素 II 和高尔基体-β1-AR 介导的高尔基体磷酸肌醇水解刺激,最终导致 PKD(蛋白激酶 D)和组蛋白去乙酰化酶 5 磷酸化减少,并防止心脏肥大:结论:这揭示了β2-AR拮抗磷脂酶Cε通路的机制,该机制可能有助于已知的β2-AR信号对心衰发展的保护作用。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
求助全文
约1分钟内获得全文 去求助
来源期刊
Circulation research
Circulation research 医学-外周血管病
CiteScore
29.60
自引率
2.00%
发文量
535
审稿时长
3-6 weeks
期刊介绍: Circulation Research is a peer-reviewed journal that serves as a forum for the highest quality research in basic cardiovascular biology. The journal publishes studies that utilize state-of-the-art approaches to investigate mechanisms of human disease, as well as translational and clinical research that provide fundamental insights into the basis of disease and the mechanism of therapies. Circulation Research has a broad audience that includes clinical and academic cardiologists, basic cardiovascular scientists, physiologists, cellular and molecular biologists, and cardiovascular pharmacologists. The journal aims to advance the understanding of cardiovascular biology and disease by disseminating cutting-edge research to these diverse communities. In terms of indexing, Circulation Research is included in several prominent scientific databases, including BIOSIS, CAB Abstracts, Chemical Abstracts, Current Contents, EMBASE, and MEDLINE. This ensures that the journal's articles are easily discoverable and accessible to researchers in the field. Overall, Circulation Research is a reputable publication that attracts high-quality research and provides a platform for the dissemination of important findings in basic cardiovascular biology and its translational and clinical applications.
期刊最新文献
Pneumonia Induced Rise in Glucagon Promotes Endothelial Damage and Thrombogenicity. LRP1 Repression by SNAIL Results in ECM Remodeling in Genetic Risk for Vascular Diseases. Kindlin-2 Phase Separation in Response to Flow Controls Vascular Stability. CAR-Macrophage Therapy Alleviates Myocardial Ischemia-Reperfusion Injury. Transformation of the Kidney into a Pathological Neuro-Immune-Endocrine Organ.
×
引用
GB/T 7714-2015
复制
MLA
复制
APA
复制
导出至
BibTeX EndNote RefMan NoteFirst NoteExpress
×
×
提示
您的信息不完整,为了账户安全,请先补充。
现在去补充
×
提示
您因"违规操作"
具体请查看互助需知
我知道了
×
提示
现在去查看 取消
×
提示
确定
0
微信
客服QQ
Book学术公众号 扫码关注我们
反馈
×
意见反馈
请填写您的意见或建议
请填写您的手机或邮箱
已复制链接
已复制链接
快去分享给好友吧!
我知道了
×
扫码分享
扫码分享
Book学术官方微信
Book学术文献互助
Book学术文献互助群
群 号:481959085
Book学术
文献互助 智能选刊 最新文献 互助须知 联系我们:info@booksci.cn
Book学术提供免费学术资源搜索服务,方便国内外学者检索中英文文献。致力于提供最便捷和优质的服务体验。
Copyright © 2023 Book学术 All rights reserved.
ghs 京公网安备 11010802042870号 京ICP备2023020795号-1