Beta Adrenergic Receptors and Focal Adhesion Cross-talk in Cardiac Remodeling

心脏重塑中的β肾上腺素能受体和局灶粘附串扰

基本信息

  • 批准号:
    7656575
  • 负责人:
  • 金额:
    $ 37.5万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2008
  • 资助国家:
    美国
  • 起止时间:
    2008-07-14 至 2012-06-30
  • 项目状态:
    已结题

项目摘要

DESCRIPTION (provided by applicant): In the heart, b-adrenergic receptors (b-AR) stimulation by catecholamines is a powerful regulatory mechanism that enhances myocardial performance in response to stress or exercise. However, sustained activation of b- AR impairs cardiac myocyte contractility and induces myocyte apoptosis, thus leading to heart failure (HF). Despite widespread acceptance that cellular contractile dysfunction and b-AR-induced HF are inter-related, the molecular mechanisms involved remain poorly understood. Integrins and focal adhesions (FA) both serve as attachment sites linking extracellular matrix (ECM) to cytoskeleton proteins and are necessary to maintain the structural integrity of the contractile apparatus as well as cardiac myocyte growth and survival. We found that early induction of eccentric hypertrophy in response to volume overload (VO) stress induced impaired FA signaling associated with enhanced interstitial collagen degradation and myocyte apoptosis. These changes were markedly reduced when animals were treated with b1-AR blockers. Certain aspects of b1-AR signaling in-vivo including FA signaling downregulation, cytoskeletal rearrangement, and myocyte apoptosis could be recapitulated in-vitro using neonatal rat cardiomyocytes (NRCMs) stimulated with b1-AR agonists. Restoration of FA signaling was sufficient to block b1-AR-induced myocyte apoptosis. This led to the hypothesis that b1- AR stimulation in response to acute VO stress promotes cardiac myocyte apoptosis through alteration of FA signaling. Aim 1 will determine the molecular mechanisms involved in FA signaling downregulation induced by sustained stimulation of b1-AR in NRCMs. Aim 2 will identify the signaling pathways downstream from FA complexes that lead to the activation of initiator caspases during b1-AR-induced myocyte apoptosis. Finally, aim 3 will determine whether b1-AR-induced alteration of FA signaling is involved in myocyte apoptosis and cardiac remodeling in response to hemodynamic stress of VO. The proposed study will integrate the novel role of FA signaling in b1-AR-induced myocyte contractile dysfunction and apoptosis that may contribute to deleterious cardiac remodeling during VO-induced HF. Understanding how these approaches achieve their effects will ultimately provide a greatest impetus for developing novel therapies for human HF. PUBLIC HEALTH RELEVANCE Beta-adrenergic receptors play a central role in the neurohumoral regulation of the heart and the progression of heart failure. The proposed study will integrate the novel role of focal adhesion signaling in beta-adrenergic receptor-induced myocyte contractile dysfunction and myocyte apoptosis that may lead to heart failure. Understanding how these approaches achieve their effects will provide a greatest impetus for developing novel therapies for human heart failure.
描述(申请人提供):在心脏中,由儿茶酚胺刺激的b-肾上腺素能受体(b-AR)是一种强大的调节机制,可以增强心肌对压力或运动的反应。然而,b-AR的持续激活会损害心肌细胞的收缩能力,诱导心肌细胞凋亡,从而导致心力衰竭(HF)。尽管人们普遍认为细胞收缩功能障碍和b-AR诱导的心衰是相互关联的,但其中涉及的分子机制仍然知之甚少。整合素和焦点粘连(FA)都是连接细胞外基质(ECM)和细胞骨架蛋白的附着部位,对维持收缩装置的结构完整性以及心肌细胞的生长和存活是必要的。我们发现,容量超负荷(VO)应激早期诱导的离心性肥厚导致FA信号受损,与间质胶原降解和心肌细胞凋亡增加有关。当动物接受b1-AR阻滞剂治疗时,这些变化明显减少。B1-AR激动剂刺激的新生大鼠心肌细胞(NRCM)在体外可以重现b1-AR信号的某些方面,包括FA信号下调、细胞骨架重排和心肌细胞凋亡。FA信号的恢复足以阻断b1-AR诱导的心肌细胞凋亡。这导致了一种假说,即刺激b1-AR以响应急性VO应激,通过改变FA信号促进心肌细胞凋亡。目的1研究b1-AR持续刺激NRCM诱导FA信号下调的分子机制。目的2将确定在b1-AR诱导的心肌细胞凋亡过程中,FA复合体下游导致启动子caspase激活的信号通路。最后,Aim 3将确定b1-AR诱导的FA信号改变是否参与VO血流动力学应激反应中的心肌细胞凋亡和心脏重构。这项拟议的研究将整合FA信号在b1-AR诱导的心肌细胞收缩功能障碍和细胞凋亡中的新作用,这些作用可能在VO诱导的心衰过程中参与有害的心脏重构。了解这些方法是如何实现其效果的,最终将为开发治疗人类心力衰竭的新疗法提供最大的推动力。与公共健康相关的β-肾上腺素能受体在心脏的神经体液调节和心力衰竭的进展中发挥核心作用。这项拟议的研究将整合粘着斑信号在β-肾上腺素能受体诱导的心肌细胞收缩功能障碍和可能导致心力衰竭的心肌细胞凋亡中的新作用。了解这些方法是如何实现其效果的,将为开发治疗人类心力衰竭的新疗法提供最大的推动力。

项目成果

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AbdelKarim Sabri其他文献

AbdelKarim Sabri的其他文献

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{{ truncateString('AbdelKarim Sabri', 18)}}的其他基金

Targeting Cbl for Cardiac Repair Post-Myocardial Infarction
靶向 Cbl 进行心肌梗死后心脏修复
  • 批准号:
    10330432
  • 财政年份:
    2019
  • 资助金额:
    $ 37.5万
  • 项目类别:
Protein activated Receptor-4 in Cardiac Rupture after Myocardial Infarction
蛋白激活受体 4 在心肌梗死后心脏破裂中的作用
  • 批准号:
    10227848
  • 财政年份:
    2018
  • 资助金额:
    $ 37.5万
  • 项目类别:
Protein activated Receptor-4 in Cardiac Rupture after Myocardial Infarction
蛋白激活受体 4 在心肌梗死后心脏破裂中的作用
  • 批准号:
    9981535
  • 财政年份:
    2018
  • 资助金额:
    $ 37.5万
  • 项目类别:
Inflammatory serine proteases and cardiac repair post myocardial infarction
炎症性丝氨酸蛋白酶与心肌梗死后的心脏修复
  • 批准号:
    9259812
  • 财政年份:
    2015
  • 资助金额:
    $ 37.5万
  • 项目类别:
Inflammatory serine proteases and cardiac repair post myocardial infarction
炎症性丝氨酸蛋白酶与心肌梗死后的心脏修复
  • 批准号:
    8942231
  • 财政年份:
    2015
  • 资助金额:
    $ 37.5万
  • 项目类别:
Beta Adrenergic Receptors and Focal Adhesion Cross-talk in Cardiac Remodeling
心脏重塑中的β肾上腺素能受体和局灶粘附串扰
  • 批准号:
    7868063
  • 财政年份:
    2008
  • 资助金额:
    $ 37.5万
  • 项目类别:
Beta Adrenergic Receptors and Focal Adhesion Cross-talk in Cardiac Remodeling
心脏重塑中的β肾上腺素能受体和局灶粘附串扰
  • 批准号:
    7527138
  • 财政年份:
    2008
  • 资助金额:
    $ 37.5万
  • 项目类别:
Beta Adrenergic Receptors and Focal Adhesion Cross-talk in Cardiac Remodeling
心脏重塑中的β肾上腺素能受体和局灶粘附串扰
  • 批准号:
    8094392
  • 财政年份:
    2008
  • 资助金额:
    $ 37.5万
  • 项目类别:
Inflammatory Proteases and Cardiac Repair after Myocardial Infarction
心肌梗塞后炎症蛋白酶与心脏修复
  • 批准号:
    8732805
  • 财政年份:
    2004
  • 资助金额:
    $ 37.5万
  • 项目类别:
Inflammmatory Proteases, Sheddases & Cardiomyocyte Death
炎症蛋白酶、脱落酶
  • 批准号:
    7095184
  • 财政年份:
    2004
  • 资助金额:
    $ 37.5万
  • 项目类别:

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