Sonodynamic Therapy Promotes Efferocytosis via CD47 Down-Regulation in Advanced Atherosclerotic Plaque
Sonodynamic Therapy Promotes Efferocytosis via CD47 Down-Regulation in Advanced Atherosclerotic Plaque
复制标题
DOI：
10.1536/ihj.21-233
复制
发表时间：
2022-01-01
影响因子：
1.5
通讯作者：
Tian, Ye
中科院分区：
文献类型：
--
作者：
Cao, Yang;Yao, Jianting;Tian, Ye
动脉粥样硬化性脑血管病是人类急性缺血性疾病的主要病因。胞浆功能受损有助于动脉粥样硬化的进展。病理细胞和凋亡细胞不能进行有效的吞噬清除，导致炎症增加和坏死核心形成。先前，我们报道了5-氨基乙酰丙酸介导的声动力疗法（SDT）通过在动脉粥样硬化斑块中释放ATP来促进凋亡细胞的efferocysis。然而，参与这一过程的确切信号分子尚不清楚。本研究采用肾卟啉钠介导的SDT （DVDMS-SDT）在兔体内进行球囊剥脱，观察动脉粥样硬化病变组成的变化。培养的人thp -1来源和小鼠腹腔巨噬细胞来源的泡沫细胞用于体外机制研究。DVDMS-SDT治疗3天后，兔动脉粥样硬化病变的巨噬细胞efferocytic明显增强，而局部炎症减轻。在第7天和第28天，组织病理学分析显示，DVDMS-SDT抑制动脉粥样硬化的进展，降低巨噬细胞含量，并呈时间依赖性地增加平滑肌细胞含量。在机制上，DVDMS-SDT激活泡沫细胞线粒体-caspase凋亡。有趣的是，在DVDMS-SDT的激活下，凋亡的关键因子caspase-3降低了泡沫细胞中抗吞噬分子CD47的表达。重要的是，DVDMS-SDT促进巨噬细胞的efferocytosis可以被CD47的过表达所消除。总之，这些结果表明，DVDMS-SDT通过使CD47表达失活，有效地促进了efferocytosis，从而减少了晚期动脉粥样硬化斑块的炎症。
Atherosclerotic cerebrocardiovascular disease is the major cause of acute ischemic diseases in humans. Impaired efferocytosis contributes to the progression of atherosclerosis. Pathological and apoptotic cells fail to undergo effective phagocytic clearance, leading to increased inflammation and necrotic core formation. Previously, we reported that 5-aminolevulinic acid-mediated sonodynamic therapy (SDT) promotes apoptotic cell efferocytosis via ATP release in atherosclerotic plaques. However, the exact signaling molecule involved in this process is still unknown. In the present study, sinoporphyrin sodium-mediated SDT (DVDMS-SDT) was applied to balloon-denuded rabbits in vivo to observe changes in the composition of atherosclerotic lesions. Cultured human THP-1-derived and mouse peritoneal macrophage-derived foam cells were used for in vitro mechanistic studies. Three days after DVDMS-SDT treatment, macrophage efferocytosis was significantly enhanced whereas local inflammation was attenuated in rabbit atherosclerotic lesions. At days 7 and 28, the histopathological analysis showed that DVDMS-SDT inhibited the progression of atherosclerosis, reduced the macrophage content, and increased the smooth muscle cell content in a time-dependent manner. Mechanistically, DVDMS-SDT activated mitochondria-caspase apoptosis in foam cells. Interestingly, activated by DVDMS-SDT, caspase-3 a key factor of apoptosis, reduced the expression of the anti-phagocytic molecule CD47 in foam cells. Of great importance, the promotion of macrophage efferocytosis by DVDMS-SDT can be eliminated by the overexpression of CD47. Overall, these results demonstrated that DVDMS-SDT effectively boosted efferocytosis via deactivation of CD47 expression, thereby reducing inflammation in advanced atherosclerotic plaques.