Serotonin receptor contribution to inflammation-induced calcific aortic valve disease

血清素受体对炎症引起的钙化主动脉瓣疾病的贡献

基本信息

  • 批准号:
    9903448
  • 负责人:
  • 金额:
    $ 39万
  • 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:
    2019-04-01 至 2023-03-31
  • 项目状态:
    已结题

项目摘要

PROJECT SUMMARY/ABSTRACT No pharmacological approach has been found to prevent/treat calcific aortic valve disease (CAVD), whose pathophysiological changes include calcification and fibrosis, causing aortic stenosis, often in combination with regurgitation. Evidence shows that pro-inflammatory cytokines are potent stimulators of cardiovascular calcification, while the serotonergic system is a potent stimulator of fibrosis. In particular, serotonin receptor 2B (SR-2B) activation is known to cause structural and mechanical changes in aortic valves, such as fibrosis and thickening, in some cases, dense nodules, though not calcification. Clinical studies also show that serotonin (5- HT) levels are almost twice as high in patients with aortic stenosis, and are significantly associated with progression of aortic stenosis. These findings suggest that SR-2B activation also contributes to the pathogenesis of inflammation-induced CAVD. Interestingly, as confirmed in our preliminary studies, the predominant receptor subtype expressed in murine aortic valve interstitial cells, at baseline, is SR-2A, rather than SR-2B. However, in our additional preliminary studies, we found that it was SR-2B that was dramatically upregulated (> 30-fold) by TNF-a. This induction required BMP-2 signaling and may account for our findings that, although 5-HT augmented TNF-a-induced calcification, it had no effect alone.. We also found that the TNF-a/5-HT-induced calcification occurred via induction of Orai1, a plasma membrane calcium channel, and this calcification was attenuated by specific inhibitors or knockdown of only SR-2B. Additional preliminary studies show that circulating peripheral 5-HT levels were higher in hyperlipidemic (Apoe-/-) compared with wild type mice, and SR-2B expression in the valve cusps was adjacent to cholesterol clefts and calcified lesions in Apoe-/- but not in wild type mice. Based on the collective evidence, we hypothesize that 5-HT in the hyperlipidemic milieu plays a key role in CAVD. We posit that hyperlipidemia increases circulating levels of both 5-HT and inflammatory cytokines, the latter of which induce SR-2B and osteogenesis in valve cusps, and, together, these events lead to CAVD. In Aim 1, we will determine receptor subtype-specific effects of 5-HT on matrix mechanics under non-inflammatory (SR-2A dominant) as well as on calcification under inflammatory (SR-2B dominant) conditions and on the signaling pathways mediating TNF-a induction of SR-2B and of downstream osteoblastic differentiation. In Aim 2, we will determine whether 5-HT signaling via SR-2B is critical for inflammation-induced CAVD using 1) a 5-HT-deficient, inflammatory mouse model (Tph1-/-Ldlr-/- Apob100/100), and 2) receptor subtype-specific agonists and antagonists. We will apply cutting edge technology, including laser light sheet fluorescence microscopy; serial in vivo fused 18F-µPET-µCT imaging; atomic force microscopy; 3-D hydrogel cultures; and implantation of receptor subtype knockdown cells. The proposed experiments will elucidate how 5-HT receptor subtype-specific signaling changes the structure of valve cusps and whether targeting SR-2B opens the path for effective pharmacological-based treatment of CAVD.
项目总结/文摘

项目成果

期刊论文数量(0)
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会议论文数量(0)
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Linda L. Demer其他文献

Artery compliance improves after ultrasonic ablation of atherosclerotic lesions
  • DOI:
    10.1016/0735-1097(90)92133-m
  • 发表时间:
    1990-02-01
  • 期刊:
  • 影响因子:
  • 作者:
    Linda L. Demer;Robert J. Siegel
  • 通讯作者:
    Robert J. Siegel

Linda L. Demer的其他文献

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{{ truncateString('Linda L. Demer', 18)}}的其他基金

Role of intermittent activation of parathyroid hormone receptor in exercise-induced vascular calcification
甲状旁腺激素受体间歇性激活在运动性血管钙化中的作用
  • 批准号:
    10534138
  • 财政年份:
    2021
  • 资助金额:
    $ 39万
  • 项目类别:
Role of intermittent activation of parathyroid hormone receptor in exercise-induced vascular calcification
甲状旁腺激素受体间歇性激活在运动性血管钙化中的作用
  • 批准号:
    10320968
  • 财政年份:
    2021
  • 资助金额:
    $ 39万
  • 项目类别:
Serotonin receptor contribution to inflammation-induced calcific aortic valve disease
血清素受体对炎症引起的钙化主动脉瓣疾病的贡献
  • 批准号:
    10365996
  • 财政年份:
    2019
  • 资助金额:
    $ 39万
  • 项目类别:
Mechanisms of intermittent parathyroid hormone effects on calcific aortic disease
间歇性甲状旁腺激素对钙化性主动脉疾病的作用机制
  • 批准号:
    9035205
  • 财政年份:
    2015
  • 资助金额:
    $ 39万
  • 项目类别:
Mechanisms of intermittent parathyroid hormone effects on calcific aortic disease
间歇性甲状旁腺激素对钙化性主动脉疾病的作用机制
  • 批准号:
    8880695
  • 财政年份:
    2015
  • 资助金额:
    $ 39万
  • 项目类别:
Role of Inhibitory SMADs in Calcific Aortic Valve Disease
抑制性 SMAD 在钙化主动脉瓣疾病中的作用
  • 批准号:
    8535813
  • 财政年份:
    2012
  • 资助金额:
    $ 39万
  • 项目类别:
Role of Inhibitory SMADs in Calcific Aortic Valve Disease
抑制性 SMAD 在钙化主动脉瓣疾病中的作用
  • 批准号:
    8891481
  • 财政年份:
    2012
  • 资助金额:
    $ 39万
  • 项目类别:
Role of Inhibitory SMADs in Calcific Aortic Valve Disease
抑制性 SMAD 在钙化主动脉瓣疾病中的作用
  • 批准号:
    8352180
  • 财政年份:
    2012
  • 资助金额:
    $ 39万
  • 项目类别:
Role of Lymphatic Clearance in Lipid-Induced Calcific Vasculopathy and Bone Loss
淋巴清除在脂质引起的钙化性血管病和骨丢失中的作用
  • 批准号:
    8165115
  • 财政年份:
    2011
  • 资助金额:
    $ 39万
  • 项目类别:
Role of Lymphatic Clearance in Lipid-Induced Calcific Vasculopathy and Bone Loss
淋巴清除在脂质引起的钙化性血管病和骨丢失中的作用
  • 批准号:
    8308373
  • 财政年份:
    2011
  • 资助金额:
    $ 39万
  • 项目类别:

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