Login Register Cart 0
Generic placeholder image

Current Pharmaceutical Design

Editor-in-Chief

ISSN (Print): 1381-6128
ISSN (Online): 1873-4286

Back
Journal Home About Journal Editorial Board Journal Insight Current Issue Volumes/Issues
Subscribe
Research Article

Cathepsin D Attenuates the Proliferation of Vascular Smooth Muscle Cells Induced by the AGE/RAGE Pathway by Suppressing the ERK Signal

Author(s): Ning Ye, Linlin Miao, Fengzhi Wang, Shaojun Wu, Boquan Wu, Ying Zhou, Chang Wang and Guozhe Sun*

Volume 29, Issue 30, 2023

Published on: 19 October, 2023

Page: [2387 - 2395] Pages: 9

DOI: 10.2174/0113816128261894231012144719

Price: $65

Abstract

Background: In this study, we aimed to clarify the role and mechanism by which Cathepsin D (CTSD) mediates the advanced glycation end products (AGEs)-induced proliferation of vascular smooth muscle cells (VSMCs).

Methods: We conducted a Western blotting assay and co-immunoprecipitation assay to detect the expression of target proteins and the interaction between different proteins. Cell Counting Kit-8 (CCK-8) assay and 5- ethynyl-2’-deoxyuridine (EdU) were used to evaluate the proliferation.

Results: AGEs significantly promoted phenotypic switching and proliferation of VSMCs in a concentration-dependent manner. This effect of AGEs was accompanied by inhibition of CTSD. Both the proliferation of VSMCs and inhibition of CTSD induced by AGEs could be attenuated by the specific inhibitor of the receptor for advanced glycation end products (RAGE), FPS-ZM1. Overexpression of CTSD significantly alleviated these effects of AGEs on VSMCs. The mechanism of CTSD action in VSMCs was also explored. Overexpression of CTSD reduced the activation of p-ERK caused by AGEs. By contrast, the knockdown of CTSD, elicited using a plasmid containing short hairpin RNA (shRNA) against CTSD, further increased the activation of p-ERK compared to AGEs alone. Additionally, co-immunoprecipitation studies revealed an endogenous interaction between CTSD, a protease, and p-ERK, its potential substrate.

Conclusion: It has been demonstrated that CTSD downregulates the level of phosphorylated ERK by degrading its target, and this interaction plays a critical role in the proliferation of VSMCs induced by the AGE/RAGE axis. These results provide a novel insight into the prevention and treatment of vascular complications in diabetes.

« Previous Next »
[1]
Jaminon A, Reesink K, Kroon A, Schurgers L. The role of vascular smooth muscle cells in arterial remodeling: Focus on calcification-related processes. Int J Mol Sci 2019; 20(22): 5694.
[http://dx.doi.org/10.3390/ijms20225694] [PMID: 31739395]
[2]
Kudryavtseva O, Aalkjær C, Matchkov VV. Vascular smooth muscle cell phenotype is defined by Ca2+-dependent transcription factors. FEBS J 2013; 280(21): 5488-99.
[http://dx.doi.org/10.1111/febs.12414] [PMID: 23848563]
[3]
Owens GK, Kumar MS, Wamhoff BR. Molecular regulation of vascular smooth muscle cell differentiation in development and disease. Physiol Rev 2004; 84(3): 767-801.
[http://dx.doi.org/10.1152/physrev.00041.2003] [PMID: 15269336]
[4]
Farina FM, Hall IF, Serio S, et al. miR-128-3p is a novel regulator of vascular smooth muscle cell phenotypic switch and vascular diseases. Circ Res 2020; 126(12): e120-35.
[http://dx.doi.org/10.1161/CIRCRESAHA.120.316489] [PMID: 32216529]
[5]
Lin H, Ni T, Zhang J, et al. Knockdown of Herp alleviates hyperhomocysteinemia mediated atherosclerosis through the inhibition of vascular smooth muscle cell phenotype switching. Int J Cardiol 2018; 269: 242-9.
[http://dx.doi.org/10.1016/j.ijcard.2018.07.043] [PMID: 30017525]
[6]
Danaei G, Finucane MM, Lu Y, et al. National, regional, and global trends in fasting plasma glucose and diabetes prevalence since 1980: Systematic analysis of health examination surveys and epidemiological studies with 370 country-years and 2.7 million participants. Lancet 2011; 378(9785): 31-40.
[http://dx.doi.org/10.1016/S0140-6736(11)60679-X] [PMID: 21705069]
[7]
Diabetes C. The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus. N Engl J Med 1993; 329(14): 977-86.
[http://dx.doi.org/10.1056/NEJM199309303291401]
[8]
Casella S, Bielli A, Mauriello A, Orlandi A. Molecular pathways regulating macrovascular pathology and vascular smooth muscle cells phenotype in type 2 diabetes. Int J Mol Sci 2015; 16(10): 24353-68.
[http://dx.doi.org/10.3390/ijms161024353] [PMID: 26473856]
[9]
Singh R, Barden A, Mori T, Beilin L. Advanced glycation end-products: A review. Diabetologia 2001; 44(2): 129-46.
[http://dx.doi.org/10.1007/s001250051591] [PMID: 11270668]
[10]
Vlassara H, Uribarri J. Advanced glycation end products (AGE) and diabetes: Cause, effect, or both? Curr Diab Rep 2014; 14(1): 453.
[http://dx.doi.org/10.1007/s11892-013-0453-1] [PMID: 24292971]
[11]
Yan SF, Ramasamy R, Schmidt AM. The RAGE axis. Circ Res 2010; 106(5): 842-53.
[http://dx.doi.org/10.1161/CIRCRESAHA.109.212217] [PMID: 20299674]
[12]
Goldin A, Beckman JA, Schmidt AM, Creager MA. Advanced glycation end products: Sparking the development of diabetic vascular injury. Circulation 2006; 114(6): 597-605.
[http://dx.doi.org/10.1161/CIRCULATIONAHA.106.621854] [PMID: 16894049]
[13]
Grimm S, Ernst L, Grötzinger N, et al. Cathepsin D is one of the major enzymes involved in intracellular degradation of AGE-modified proteins. Free Radic Res 2010; 44(9): 1013-26.
[http://dx.doi.org/10.3109/10715762.2010.495127] [PMID: 20560835]
[14]
Grimm S, Horlacher M, Catalgol B, Hoehn A, Reinheckel T, Grune T. Cathepsins D and L reduce the toxicity of advanced glycation end products. Free Radic Biol Med 2012; 52(6): 1011-23.
[http://dx.doi.org/10.1016/j.freeradbiomed.2011.12.021] [PMID: 22245096]
[15]
Ma M, Guo X, Chang Y, et al. Advanced glycation end products promote proliferation and suppress autophagy via reduction of Cathepsin D in rat vascular smooth muscle cells. Mol Cell Biochem 2015; 403(1-2): 73-83.
[http://dx.doi.org/10.1007/s11010-015-2338-x] [PMID: 25673507]
[16]
Li C, Chang Y, Li Y, et al. Advanced glycation end products promote the proliferation and migration of primary rat vascular smooth muscle cells via the upregulation of BAG3. Int J Mol Med 2017; 39(5): 1242-54.
[http://dx.doi.org/10.3892/ijmm.2017.2938] [PMID: 28350077]
[17]
Cao C, Luo X, Ji X, et al. Osteopontin regulates the proliferation of rat aortic smooth muscle cells in response to gingipains treatment. Mol Cell Probes 2017; 33: 51-6.
[http://dx.doi.org/10.1016/j.mcp.2017.03.003] [PMID: 28302392]
[18]
Ajith TA, Vinodkumar P. Advanced glycation end products: Association with the pathogenesis of diseases and the current therapeutic advances. Curr Clin Pharmacol 2016; 11(2): 118-27.
[http://dx.doi.org/10.2174/1574884711666160511150028] [PMID: 27164965]
[19]
Jud P, Sourij H. Therapeutic options to reduce advanced glycation end products in patients with diabetes mellitus: A review. Diabetes Res Clin Pract 2019; 148: 54-63.
[http://dx.doi.org/10.1016/j.diabres.2018.11.016] [PMID: 30500546]
[20]
Yang P, Feng J, Peng Q, Liu X, Fan Z. Advanced glycation end products: Potential mechanism and therapeutic target in cardiovascular complications under diabetes. Oxid Med Cell Longev 2019; 2019: 1-12.
[http://dx.doi.org/10.1155/2019/9570616] [PMID: 31885827]
[21]
Xin H, Wang Z, Wu S, et al. Calcified decellularized arterial scaffolds impact vascular smooth muscle cell transformation via downregulating α-SMA expression and upregulating OPN expression. Exp Ther Med 2019; 18(1): 705-10.
[http://dx.doi.org/10.3892/etm.2019.7626] [PMID: 31281450]
[22]
Fusek M, Větvička V. Dual role of cathepsin D: Ligand and protease. Biomed Pap Med Fac Univ 2005; 149(1): 43-50.
[http://dx.doi.org/10.5507/bp.2005.003] [PMID: 16170387]
[23]
Gan P, Xia Q, Hang G, et al. Knockdown of cathepsin D protects dopaminergic neurons against neuroinflammation-mediated neurotoxicity through inhibition of NF-κB signalling pathway in Parkinson’s disease model. Clin Exp Pharmacol Physiol 2019; 46(4): 337-49.
[http://dx.doi.org/10.1111/1440-1681.13052] [PMID: 30485484]
[24]
Lee KP, Kim JE, Kim H, Chang HR, Lee DW, Park WH. Bo- Gan-Whan regulates proliferation and migration of vascular smooth muscle cells. BMC Complement Altern Med 2016; 16(1): 306.
[http://dx.doi.org/10.1186/s12906-016-1292-9] [PMID: 27549769]
[25]
Peng H, Zhang K, Liu Z, et al. VPO1 modulates vascular smooth muscle cell phenotypic switch by activating extracellular signal-regulated kinase 1/2 (ERK 1/2) in abdominal aortic aneurysms. J Am Heart Assoc 2018; 7(17): e010069.
[http://dx.doi.org/10.1161/JAHA.118.010069] [PMID: 30371171]
[26]
Takei Y, Higashira H, Yamamoto T, Hayashi K. Mitogenic activity toward human breast cancer cell line MCF-7 of two bFGFs purified from sera of breast cancer patients: Co-operative role of cathepsin D. Breast Cancer Res Treat 1997; 43(1): 53-63.
[http://dx.doi.org/10.1023/A:1005749925296] [PMID: 9065599]
[27]
Hakala JK, Oksjoki R, Laine P, et al. Lysosomal enzymes are released from cultured human macrophages, hydrolyze LDL in vitro, and are present extracellularly in human atherosclerotic lesions. Arterioscler Thromb Vasc Biol 2003; 23(8): 1430-6.
[http://dx.doi.org/10.1161/01.ATV.0000077207.49221.06] [PMID: 12750117]
[28]
Handley CJ, Tuck Mok M, Ilic MZ, Adcocks C, Buttle DJ, Robinson HC. Cathepsin D cleaves aggrecan at unique sites within the interglobular domain and chondroitin sulfate attachment regions that are also cleaved when cartilage is maintained at acid pH. Matrix Biol 2001; 20(8): 543-53.
[http://dx.doi.org/10.1016/S0945-053X(01)00168-8] [PMID: 11731271]
[29]
Piwnica D, Touraine P, Struman I, et al. Cathepsin D processes human prolactin into multiple 16K-like N-terminal fragments: Study of their antiangiogenic properties and physiological relevance. Mol Endocrinol 2004; 18(10): 2522-42.
[http://dx.doi.org/10.1210/me.2004-0200] [PMID: 15192082]
[30]
Wolf M, Clark-Lewis I, Buri C, Langen H, Lis M, Mazzucchelli L. Cathepsin D specifically cleaves the chemokines macrophage inflammatory protein-1 alpha, macrophage inflammatory protein-1 beta, and SLC that are expressed in human breast cancer. Am J Pathol 2003; 162(4): 1183-90.
[http://dx.doi.org/10.1016/S0002-9440(10)63914-4] [PMID: 12651610]

Rights & Permissions Print Cite
© 2024 Bentham Science Publishers | Privacy Policy