Chinese Medical Sciences Journal ›› 2010, Vol. 25 ›› Issue (2): 76-84.doi: 10.1016/S1001-9294(10)60026-0

• Original Article • Previous Articles     Next Articles

Lipids-induced Apoptosis Is Aggravated by Acyl-coenzyme A: Cholesterol Acyltransferase Inhibitor

Jian-ling Tao1, Xiong-zhong Ruan2, Hang Li1, Xue-mei Li1, and Xue-wang Li1*   

  1. 1Department of Nephrology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100730, China 2Centre for Nephrology, University College London Medical School, Royal Free Campus, London, NW3 2PF, UK
  • Received:2010-01-20 Online:2010-06-10 Published:2010-06-10
  • About author:Tel: 86-10-65295058
  • Supported by:

    Supported by National Natural Science Foundation of China (30700373).

Abstract: Objective To investigate the role of acyl-coenzyme A: cholesterol acyltransferase inhibitor (ACATI) in apoptosis induced by lipids and whether lipids-induced apoptosis is accompanied by increase of free cholesterol in endoplasmic reticulum (ER), in order to further understand the mechanism of lipids-induced apoptosis in advanced atherosclerosis. Methods Human vascular smooth muscle cells (VSMCs) and phorbol 12-myristate 13-acetate (PMA) differentiated THP-1 macrophages were used. Tritiated thymidine incorporation was applied to detect cell proliferation. Cytotoxicity was assessed by lactate dehydrogenase (LDH) release. 4',6-diamidino-2-phenylindole (DAPI) staining, caspase-3, -7 assay, and Annexin-V/propidium iodide (PI) staining were used to detect apoptosis. High performance liquid chromatography was used in intracellular free cholesterol and cholesterol ester assay. ER free cholesterol was quantified. Results Different lipids had different effects on proliferation and cytotoxicity of VSMCs. 25-hydroxycholesterol (25OHC) had biphasic effects on the proliferation of VSMCs. At low concentration, it stimulated cell proliferation, but turned to proliferation inhibition as concentration reached 15 ug/mL. 25OHC and acetylated low density lipoprotein (AcLDL) could respectively induce apoptosis in human VSMCs and PMA differentiated THP-1 macrophages, which was aggravated by ACATI, accompanied by increase of intracellular free cholesterol content. There was also an increase of cholesterol content in ER with AcLDL-induced apoptosis in THP-1 macrophages. Conclusions Lipids could induce apoptosis, accompanied by increase of intracellular free cholesterol content, which could be augmented by ACATI, suggesting that insults resulting in ER free cholesterol rise might be the initiator of apoptosis.

Key words: apoptosis, atherosclerosis, acyl-coenzyme A: cholesterol acyltransferase

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