Cathepsin L stimulates autophagy and inhibits apoptosis of ox-LDL-induced endothelial cells: Potential role in atherosclerosis

Wei,Dang-Heng; Jia,Xiao-Ying; Liu,Yang-Hui; Guo,Feng-Xia; Tang,Zhi-Han; Li,Xiao-Hong; Wang,Zuo; Liu,Lu-Shan; Wang,Gui-Xue; Jian,Zhi-Sheng; Ruan,Chang-Geng

doi:10.3892/ijmm.2012.1201

February 2013 Volume 31 Issue 2

Full Size Image

Journals

International Journal of Molecular Medicine

International Journal of Molecular Medicine is an international journal devoted to molecular mechanisms of human disease.

International Journal of Oncology

International Journal of Oncology is an international journal devoted to oncology research and cancer treatment.

Molecular Medicine Reports

Covers molecular medicine topics such as pharmacology, pathology, genetics, neuroscience, infectious diseases, molecular cardiology, and molecular surgery.

Oncology Reports

Oncology Reports is an international journal devoted to fundamental and applied research in Oncology.

Experimental and Therapeutic Medicine

Experimental and Therapeutic Medicine is an international journal devoted to laboratory and clinical medicine.

Oncology Letters

Oncology Letters is an international journal devoted to Experimental and Clinical Oncology.

Biomedical Reports

Explores a wide range of biological and medical fields, including pharmacology, genetics, microbiology, neuroscience, and molecular cardiology.

Molecular and Clinical Oncology

International journal addressing all aspects of oncology research, from tumorigenesis and oncogenes to chemotherapy and metastasis.

World Academy of Sciences Journal

Multidisciplinary open-access journal spanning biochemistry, genetics, neuroscience, environmental health, and synthetic biology.

International Journal of Functional Nutrition

Open-access journal combining biochemistry, pharmacology, immunology, and genetics to advance health through functional nutrition.

International Journal of Epigenetics

Publishes open-access research on using epigenetics to advance understanding and treatment of human disease.

Medicine International

An International Open Access Journal Devoted to General Medicine.

February 2013 Volume 31 Issue 2

Full Size Image

Article

Cathepsin L stimulates autophagy and inhibits apoptosis of ox-LDL-induced endothelial cells: Potential role in atherosclerosis

Authors:
- Dang-Heng Wei
- Xiao-Ying Jia
- Yang-Hui Liu
- Feng-Xia Guo
- Zhi-Han Tang
- Xiao-Hong Li
- Zuo Wang
- Lu-Shan Liu
- Gui-Xue Wang
- Zhi-Sheng Jian
- Chang-Geng Ruan
View Affiliations / Copyright

Affiliations: Institute of Cardiovascular Disease, Key Laboratory for Arteriosclerology of Hunan Province, University of South China, Hengyang 421001, P.R. China, Key Laboratory of Biorheological Science and Technology (Chongqing University), Ministry of Education, Bioengineering College of Chongqing University, Chongqing 400044, P.R. China, First Affiliated Hospital of Soochow University, Jiangsu Institute of Hematology, Key Laboratory of Thrombosis and Hemostasis, Ministry of Health, Suzhou 215006, P.R. China
Pages: 400-406
|
Published online on: December 3, 2012

https://doi.org/10.3892/ijmm.2012.1201
Expand metrics +

Abstract

The activation of endothelial cells by oxidized low-density lipoprotein (ox-LDL) with subsequent increases in endothelial permeability occurs in the early stage of atherosclerosis. Cathepsin L (CATL) is one of the cysteine proteases and has been implicated in advanced atherosclerotic lesions and plaque instability. This study aimed to explore the role of CATL in ox-LDL-induced early atherosclerotic events and to delineate the underlying mechanism. Results showed that ox-LDL upregulated CATL protein levels and activation in human umbilical vein endothelial cells (ECs) in a concentration-dependent manner and stimulated EC autophagy and apoptosis and increased EC monolayer permeability. Concomitantly, VE-cadherin expression was decreased. When ECs were pretreated with a CATL inhibitor, ox-LDL-induced autophagy was inhibited while apoptosis was further increased. In addition, the VE-cadherin protein level was increased, and the EC monolayer permeability was reduced. Taken together, the present study showed that the upregulated expression and activation of CATL induced by ox-LDL, increased EC autophagy and antagonized EC apoptosis, which partly neutralized the effect of increased EC monolayer permeability mediated by the downregulation of VE-cadherin. Thus, the proatherogenic effect of CATL was partly neutralized by inducing autophagy and inhibiting apoptosis in early stages of atherosclerosis.

View Figures

View References

1.	Koch S and Nusrat A: Dynamic regulation of epithelial cell fate and barrier function by intercellular junctions. Ann NY Acad Sci. 1165:220–227. 2009. View Article : Google Scholar : PubMed/NCBI
2.	Tarbell JM: Mass transport in arteries and the localization of atherosclerosis. Annu Rev Biomed Eng. 5:79–118. 2003. View Article : Google Scholar : PubMed/NCBI
3.	Jormsjo S, Wuttge DM, Sirsjo A, Whatling C, Hamsten A, Stemme S and Eriksson P: Differential expression of cysteine and aspartic proteases during progression of atherosclerosis in apolipoprotein E-deficient mice. Am J Pathol. 161:939–945. 2002. View Article : Google Scholar : PubMed/NCBI
4.	Rebbaa A, Chu F, Sudha T, Gallati C, Dier U, Dyskin E, Yalcin M, Bianchini C, Shaker O and Mousa SA: The anti-angiogenic activity of NSITC, a specific cathepsin L inhibitor. Anticancer Res. 29:4473–4481. 2009.PubMed/NCBI
5.	Mahmood DF, Jguirim-Souissi I, Khadija el-H, Blondeau N, Diderot V, Amrani S, Slimane MN, Syrovets T, Simmet T and Rouis M: Peroxisome proliferator-activated receptor gamma induces apoptosis and inhibits autophagy of human monocyte-derived macrophages via induction of cathepsin L: potential role in atherosclerosis. J Biol Chem. 286:28858–28866. 2011. View Article : Google Scholar
6.	Cancel LM and Tarbell JM: The role of apoptosis in LDL transport through cultured endothelial cell monolayers. Atherosclerosis. 208:335–341. 2010. View Article : Google Scholar : PubMed/NCBI
7.	Chen KL, Chang WS, Cheung CH, Lin CC, Huang CC, Yang YN, Kuo CP, Kuo CC, Chang YH, Liu KJ, Wu CM and Chang JY: Targeting cathepsin S induces tumor cell autophagy via the EGFR-ERK signaling pathway. Cancer Lett. 317:89–98. 2012. View Article : Google Scholar : PubMed/NCBI
8.	Bhoopathi P, Chetty C, Gujrati M, Dinh DH, Rao JS and Lakka S: Cathepsin B facilitates autophagy-mediated apoptosis in SPARC overexpressed primitive neuroectodermal tumor cells. Cell Death Differ. 17:1529–1539. 2010. View Article : Google Scholar
9.	Ouimet M, Franklin V, Mak E, Liao X, Tabas I and Marcel YL: Autophagy regulates cholesterol efflux from macrophage foam cells via lysosomal acid lipase. Cell Metab. 13:655–667. 2011. View Article : Google Scholar : PubMed/NCBI
10.	Zhang YL, Cao YJ, Zhang X, Liu HH, Tong T, Xiao GD, Yang YP and Liu CF: The autophagy-lysosome pathway: a novel mechanism involved in the processing of oxidized LDL in human vascular endothelial cells. Biochem Biophys Res Commun. 394:377–382. 2010. View Article : Google Scholar : PubMed/NCBI
11.	Liao X, Sluimer JC, Wang Y, Subramanian M, Brown K, Pattison JS, Robbins J, Martinez J and Tabas I: Macrophage autophagy plays a protective role in advanced atherosclerosis. Cell Metab. 15:545–553. 2012. View Article : Google Scholar : PubMed/NCBI
12.	Mei S, Gu H, Ward A, Yang X, Guo H, He K, Liu Z and Cao W: p38 mitogen-activated protein kinase (MAPK) promotes cholesterol ester accumulation in macrophages through inhibition of macroautophagy. J Biol Chem. 287:11761–11768. 2012. View Article : Google Scholar : PubMed/NCBI
13.	Zhaorigetu S, Yang Z, Toma I, McCaffrey TA and Hu CA: Apolipoprotein L6, induced in atherosclerotic lesions, promotes apoptosis and blocks Beclin 1-dependent autophagy in atherosclerotic cells. J Biol Chem. 286:27389–27398. 2011. View Article : Google Scholar : PubMed/NCBI
14.	Xie Y, You SJ, Zhang YL, Han Q, Cao YJ, Xu XS, Yang YP, Li J and Liu CF: Protective role of autophagy in AGE-induced early injury of human vascular endothelial cells. Mol Med Rep. 4:459–464. 2011.PubMed/NCBI
15.	Martinet W and De Meyer GR: Autophagy in atherosclerosis. Curr Atheroscler Rep. 10:216–223. 2008. View Article : Google Scholar
16.	Dennemärker J, Lohmüller T, Müller S, Aguilar SV, Tobin DJ, Peters C and Reinheckel T: Impaired turnover of autophagolysosomes in cathepsin L deficiency. Biol Chem. 391:913–922. 2010.PubMed/NCBI
17.	Wirawan E, Vande Walle L, Kersse K, Cornelis S, Claerhout S, Vanoverberghe I, Roelandt R, De Rycke R, Verspurten J, Declercq W, Agostinis P, Vanden Berghe T, Lippens S and Vandenabeele P: Caspase-mediated cleavage of Beclin-1 inactivates Beclin-1-induced autophagy and enhances apoptosis by promoting the release of proapoptotic factors from mitochondria. Cell Death Dis. 1:e182010. View Article : Google Scholar : PubMed/NCBI
18.	Sakamoto N, Segawa K, Kanzaki M, Ohashi T and Sato M: Role of p120-catenin in the morphological changes of endothelial cells exposed to fluid shear stress. Biochem Biophys Res Commun. 398:426–432. 2010. View Article : Google Scholar : PubMed/NCBI

Journals

International Journal of Molecular Medicine

International Journal of Oncology

Molecular Medicine Reports

Oncology Reports

Experimental and Therapeutic Medicine

Oncology Letters

Biomedical Reports

Molecular and Clinical Oncology

World Academy of Sciences Journal

International Journal of Functional Nutrition

International Journal of Epigenetics

Medicine International

Cathepsin L stimulates autophagy and inhibits apoptosis of ox-LDL-induced endothelial cells: Potential role in atherosclerosis

This article is mentioned in:

Abstract

Figure 1

Figure 2

Figure 3

Figure 4

Figure 5

Figure 6

Figure 7

Related Articles