通过C-反应蛋白进行剪切感应:将大动脉狭窄和炎症联系起来
Johannes Zeller1,2, Julia Loseff-Silver1, Khashayar Khoshmanesh3
1Atherothrombosis and Vascular Biology Laboratory, Baker Heart and Diabetes Institute, Melbourne, Victoria, Australia (J.Z., J.L.-S., S.B., A.L., A.R., A. Watson, N.D., P.S., A.B.-W., Y.C.C., M.M., M.L.P.V., A.H., N.M.H., X.W., G.P., J.D.M., K.P.).
Circulation research
|October 18, 2024
概括
剪切压力导致C反应蛋白 (CRP) 分离成炎性单体 (mCRP),导致大动脉狭窄 (AS). 这种解离激活了参与AS发展和其他血管疾病的细胞.
科学领域:
- 心血管生物学 心血管生物学
- 蛋白质生物化学 蛋白质生物化学
- 机械生物学 机械生物学
背景情况:
- C-反应性蛋白 (CRP) 存在于 pentameric 形式 (pCRP),但可以分解成单体子单元 (mCRP).
- 单体CRP (mCRP) 具有前血栓和前炎性质.
- 病理生理剪切率,常见于大动脉狭窄症 (AS),可以改变蛋白质结构和功能.
研究的目的:
- 调查剪切应力是否会改变CRP形状,并诱导与AS病变发生相关的炎症效应.
- 探索剪切诱导的CRP解离在AS发展中的作用.
主要方法:
- 在实验室中将人类pCRP置于病理生理学上相关的剪切速率下.
- 使用生物物理和生物化学分析来评估CRP的结构和功能.
- 采用动脉狭窄的小鼠模型来研究体内剪切效应.
- 在重症AS患者中测量mCRP和pCRP水平,在穿透导管大动脉植入之前和之后.
- 检查在切除的狭窄性大动脉上存在CRP.
- 使用微流体模型模拟AS切割速率并调查mCRP的炎症功能.
主要成果:
- 高剪切速率诱导pCRP分裂成mCRP,并聚合成更大的颗粒.
- 在体内研究证实了在小鼠模型中静脉缩小后的mCRP沉积.
- 在AS患者显示高循环mCRP水平在transcatheter主动脉植入前.
- 切除的人类狭性大动脉门显示mCRP沉积.
- 在微流体AS模型中,切削压力pCRP激活了内皮细胞 (增加ICAM-1,P-选择蛋白) 和血小板 (增加TGF-β).
结论:
- 鉴定了一种新的剪切诱导的pCRP分裂到mCRP的机制,激活AS发展中的关键细胞.
- 这种pCRP解离的机械感知机制可能与其他与剪切率增加的疾病相关,例如动脉样硬化.
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