Dept of Biomedical Engineering, Zhejiang University, Key Laboratory of Biomedical Engineering of Ministry of Education, Zheda Road 38, Hangzhou, 310027, Zhejiang, China.
Atherosclerosis. 2009 Nov;207(1):123-30. doi: 10.1016/j.atherosclerosis.2009.04.019. Epub 2009 Apr 24.
Smooth muscle cells (SMCs) death promotes atherosclerotic lesion necrosis and plaque destabilization. We investigated the potential mechanisms of rat SMCs death in response to excess free cholesterol (FC).
Rat aortic SMCs were incubated with "water soluble cholesterol" and acyl-CoA:cholesterol acyltransferase (ACAT) inhibitor Sandoz58035 to establish FC-overloading cell model. Disruption of mitochondrial network and endoplasmic reticulum (ER) was observed after 12h incubation by transient transfection. After treated for 24h, enhanced cell death was noted as detected by propidium iodide (PI) staining/flow cytometry (P<0.001 vs. control). SMCs death was associated with markedly decreased mitochondrial transmembrane potential (Deltaphim), as well as upregulation of cellular reactive oxygen species (ROS) and ER stress. We also investigated possible signaling pathways involved in excess FC-initiated cell death and found that unfolded protein response (UPR) was activated, with increased cellular Bax expression and release of mitochondrial cytochrome c.
Our findings suggested that FC-overloading might trigger SMCs death. Both ER- and mitochondria-based signals might be implicated in these lethal events.
平滑肌细胞（SMC）的死亡会促进动脉粥样硬化病变的坏死和斑块不稳定。我们研究了大鼠 SMC 对过量游离胆固醇（FC）反应性死亡的潜在机制。
用“水溶性胆固醇”和酰基辅酶 A：胆固醇酰基转移酶（ACAT）抑制剂 Sandoz58035孵育大鼠主动脉 SMC，建立 FC 超负荷细胞模型。瞬时转染后观察到线粒体网络和内质网（ER）破坏在孵育 12 小时后发生。孵育 24 小时后，用碘化丙啶（PI）染色/流式细胞术（PI staining/flow cytometry，PI/F）检测到细胞死亡明显增加（P<0.001 与对照组相比）。SMC 死亡与线粒体跨膜电位（Deltaphim）显著降低以及细胞活性氧（ROS）和 ER 应激的上调有关。我们还研究了过量 FC 引发细胞死亡所涉及的可能信号通路，发现未折叠蛋白反应（UPR）被激活，细胞 Bax 表达增加，线粒体细胞色素 c 释放。
我们的研究结果表明，FC 超负荷可能引发 SMC 死亡。内质网和线粒体信号都可能参与这些致死事件。
