YY-11, a camel milk-derived peptide, inhibits TGF-β-mediated atherogenic signaling in human vascular smooth muscle cells
Humaira Hussain
School of Pharmacy, University of Queensland, Pharmacy Australia Centre of Excellence, Woolloongabba, QLD, Australia
Department of Biochemistry and Biotechnology, Arid Agriculture University, Rawalpindi, Pakistan
Contribution: Writing - original draft
Search for more papers by this authorYingnan Cao
Department of Pharmacy, Xinhua College of Sun Yat-sen University, Guangzhou, China
Search for more papers by this authorRaafat Mohamad
School of Pharmacy, University of Queensland, Pharmacy Australia Centre of Excellence, Woolloongabba, QLD, Australia
Search for more papers by this authorRizwana Afroz
School of Pharmacy, University of Queensland, Pharmacy Australia Centre of Excellence, Woolloongabba, QLD, Australia
Contribution: Writing - review & editing
Search for more papers by this authorYing Zhou
School of Pharmacy, University of Queensland, Pharmacy Australia Centre of Excellence, Woolloongabba, QLD, Australia
Contribution: Writing - original draft
Search for more papers by this authorPeter Moyle
School of Pharmacy, University of Queensland, Pharmacy Australia Centre of Excellence, Woolloongabba, QLD, Australia
Contribution: Writing - review & editing
Search for more papers by this authorNidhi Bansal
School of Agriculture and Food Sciences, Faculty of Science, University of Queensland, St. Lucia, QLD, Australia
Contribution: Writing - review & editing
Search for more papers by this authorFeroza Hamid Wattoo
Department of Biochemistry and Biotechnology, Arid Agriculture University, Rawalpindi, Pakistan
Contribution: Supervision
Search for more papers by this authorDanielle Kamato
School of Pharmacy, University of Queensland, Pharmacy Australia Centre of Excellence, Woolloongabba, QLD, Australia
Department of Pharmacy, Xinhua College of Sun Yat-sen University, Guangzhou, China
Contribution: Writing - review & editing
Search for more papers by this authorCorresponding Author
Peter J. Little
School of Pharmacy, University of Queensland, Pharmacy Australia Centre of Excellence, Woolloongabba, QLD, Australia
Department of Pharmacy, Xinhua College of Sun Yat-sen University, Guangzhou, China
Correspondence
Peter J. Little, School of Pharmacy, The University of Queensland, 20 Cornwall Street, Woolloongabba, QLD 4102, Australia.
Email: [email protected]
Search for more papers by this authorHumaira Hussain
School of Pharmacy, University of Queensland, Pharmacy Australia Centre of Excellence, Woolloongabba, QLD, Australia
Department of Biochemistry and Biotechnology, Arid Agriculture University, Rawalpindi, Pakistan
Contribution: Writing - original draft
Search for more papers by this authorYingnan Cao
Department of Pharmacy, Xinhua College of Sun Yat-sen University, Guangzhou, China
Search for more papers by this authorRaafat Mohamad
School of Pharmacy, University of Queensland, Pharmacy Australia Centre of Excellence, Woolloongabba, QLD, Australia
Search for more papers by this authorRizwana Afroz
School of Pharmacy, University of Queensland, Pharmacy Australia Centre of Excellence, Woolloongabba, QLD, Australia
Contribution: Writing - review & editing
Search for more papers by this authorYing Zhou
School of Pharmacy, University of Queensland, Pharmacy Australia Centre of Excellence, Woolloongabba, QLD, Australia
Contribution: Writing - original draft
Search for more papers by this authorPeter Moyle
School of Pharmacy, University of Queensland, Pharmacy Australia Centre of Excellence, Woolloongabba, QLD, Australia
Contribution: Writing - review & editing
Search for more papers by this authorNidhi Bansal
School of Agriculture and Food Sciences, Faculty of Science, University of Queensland, St. Lucia, QLD, Australia
Contribution: Writing - review & editing
Search for more papers by this authorFeroza Hamid Wattoo
Department of Biochemistry and Biotechnology, Arid Agriculture University, Rawalpindi, Pakistan
Contribution: Supervision
Search for more papers by this authorDanielle Kamato
School of Pharmacy, University of Queensland, Pharmacy Australia Centre of Excellence, Woolloongabba, QLD, Australia
Department of Pharmacy, Xinhua College of Sun Yat-sen University, Guangzhou, China
Contribution: Writing - review & editing
Search for more papers by this authorCorresponding Author
Peter J. Little
School of Pharmacy, University of Queensland, Pharmacy Australia Centre of Excellence, Woolloongabba, QLD, Australia
Department of Pharmacy, Xinhua College of Sun Yat-sen University, Guangzhou, China
Correspondence
Peter J. Little, School of Pharmacy, The University of Queensland, 20 Cornwall Street, Woolloongabba, QLD 4102, Australia.
Email: [email protected]
Search for more papers by this authorAbstract
Atherosclerosis, the major underlying pathology of cardiovascular disease, commences with the binding and trapping of lipids on modified proteoglycans, with hyperelongated glycosaminoglycan chains. Transforming growth factor (TGF)-β stimulates glycosaminoglycan elongation in vascular smooth muscle cells. We have recently shown that this TGF-β signaling pathway involves reactive oxygen species (ROS). YY-11 is a dodecapeptide derived from camel milk and it has antioxidant activity. We have investigated the role of YY-11 in blocking ROS signaling and downstream atherogenic responses. YY-11 inhibited TGF-β stimulated ROS production and inhibited the expression of genes for glycosaminoglycan chain elongation as a component of an in vitro model of atherosclerosis. This study provides a biochemical mechanism for the role of camel milk as a potential nutritional product to contribute to the worldwide amelioration of cardiovascular disease.
Practical applications
The identification of readily accessible foods with antioxidant properties would provide a convenient and cost-effective approach community wide reducing oxidative stress induced pathologies such as atherosclerosis. We demonstrate that camel milk-derived peptide is an antioxidant that can inhibit growth factor-mediated proteoglycan modification in vitro. As proteoglycan modification is being recognized as one of the earliest atherogenic responses, these data support the notion of camel milk as a suitable nutritional product to contribute to the prevention of early stage of atherosclerosis development.
CONFLICT OF INTEREST
The authors declared that they have no conflict of interest.
REFERENCES
- Abbas, S., Ashraf, H., Nazir, A., & Sarfraz, L. (2013). Physico-chemical analysis and composition of camel milk. International Research, 2(2), 85–98.
- Adelman, J., & Haushofer, L. (2018). Introduction: Food as medicine, medicine as food. Journal of the History of Medicine and Allied Sciences, 73(2), 127–134. https://doi.org/10.1093/jhmas/jry010
- Afroz, R., Cao, Y., Rostam, M. A., Ta, H., Xu, S., Zheng, W., Osman, N., Kamato, D., & Little, P. J. (2018). Signalling pathways regulating galactosaminoglycan synthesis and structure in vascular smooth muscle: Implications for lipoprotein binding and atherosclerosis. Pharmacology & Therapeutics, 187, 88–97.
- Afroz, R., Zhou, Y., Little, P. J., Xu, S., Mohamed, R., Stow, J., & Kamato, D. (2020). Toll-like receptor 4 stimulates gene expression via Smad2 linker region phosphorylation in vascular smooth muscle cells. ACS Pharmacology & Translational Science, 3(3), 524–534. https://doi.org/10.1021/acsptsci.9b00113
- Ballinger, M. L., Osman, N., Hashimura, K., de Hann, J., Jandeleit-Dahm, K., Allen, T. J., Tannock, L. R., Rutledge, J. C., & Little, P. J. (2010). Imatinib inhibits vascular smooth muscle proteoglycan synthesis and reduces LDL binding in vitro and aortic lipid deposition in vivo. Journal of Cellular and Molecular Medicine, 14, 1408–1418.
- Bobik, A., Agrotis, A., Kanellakis, P., Dilley, R., Krushinsky, A., Smirnov, V., Tararak, E., Condron, M., & Kostolias, G. (1999). Distinct patterns of transforming growth factor-beta isoform and receptor expression in human atherosclerotic lesions. Colocalization implicates TGF-beta in fibrofatty lesion development. Circulation, 99(22), 2883–2891.
- Burch, M. L., Yang, S. N., Ballinger, M. L., Getachew, R., Osman, N., & Little, P. J. (2010). TGF-β stimulates biglycan synthesis via p38 and ERK phosphorylation of the linker region of Smad2. Cellular and Molecular Life Sciences, 67(12), 2077–2090. https://doi.org/10.1007/s00018-010-0315-9
- Getachew, R., Ballinger, M. L., Burch, M. L., Little, P. J., & Osman, N. (2010). Characterisation of Ki11502 as a potent inhibitor of PDGF beta receptor-mediated proteoglycan synthesis in vascular smooth muscle cells. European Journal of Pharmacology, 626(2–3), 186–192.
- Homayouni-Tabrizi, M., Asoodeh, A., & Soltani, M. (2017). Cytotoxic and antioxidant capacity of camel milk peptides: Effects of isolated peptide on superoxide dismutase and catalase gene expression. Journal of Food and Drug Analysis, 25(3), 567–575. https://doi.org/10.1016/j.jfda.2016.10.014
- Homayouni-Tabrizi, M., Shabestarin, H., Asoodeh, A., & Soltani, M. (2016). Identification of two novel antioxidant peptides from camel milk using digestive proteases: Impact on expression gene of superoxide dismutase (SOD) in hepatocellular carcinoma cell line. International Journal of Peptide Research and Therapeutics, 22(2), 187–195. https://doi.org/10.1007/s10989-015-9497-1
- Ibrahim, H. R., Isono, H., & Miyata, T. (2018). Potential antioxidant bioactive peptides from camel milk proteins. Animal Nutrition (Zhongguo Xu Mu Shou Yi Xue hui), 4(3), 273–280. https://doi.org/10.1016/j.aninu.2018.05.004
- Kamato, D., Burch, M. L., Piva, T. J., Rezaei, H. B., Rostam, M. A., Xu, S., Zheng, W., Little, P. J., & Osman, N. (2013). Transforming growth factor-beta signalling: Role and consequences of Smad linker region phosphorylation. Cellular Signalling, 25(10), 2017–2024.
- Kamato, D., Burch, M., Zhou, Y., Mohamed, R., Stow, J. L., Osman, N., Zheng, W., & Little, P. J. (2019). Individual Smad2 linker region phosphorylation sites determine the expression of proteoglycan and glycosaminoglycan synthesizing genes. Cellular Signalling, 53, 365–373.
- Kamato, D., Do, B. H., Osman, N., Ross, B. P., Mohamed, R., Xu, S., & Little, P. J. (2020). Smad linker region phosphorylation is a signalling pathway in its own right and not only a modulator of canonical TGF-beta signalling. Cellular and Molecular Life Sciences, 77(2), 243–251.
- Kamato, D., & Little, P. J. (2020). Smad2 linker region phosphorylation is an autonomous cell signalling pathway: Implications for multiple disease pathologies. Biomedicine & Pharmacotherapy, 124, 109854.
- Kamato, D., Ta, H., Afroz, R., Xu, S., Osman, N., & Little, P. J. (2019). Mechanisms of PAR-1 mediated kinase receptor transactivation: Smad linker region phosphorylation. Journal of Cell Communication and Signaling, 13(4), 539–548. https://doi.org/10.1007/s12079-019-00527-5
- Kamato, D., Thach, L., Getachew, R., Burch, M., Hollenberg, M. D., Zheng, W., Little, P. J., & Osman, N. (2016). Protease activated receptor-1 mediated dual kinase receptor transactivation stimulates the expression of glycosaminoglycan synthesizing genes. Cellular Signalling, 28(1), 110–119. https://doi.org/10.1016/j.cellsig.2015.11.003
- Libby, P. (2006). Inflammation and cardiovascular disease mechanisms. American Journal of Clinical Nutrition, 83(2), 456S–460S.
- Liu, Z., Wang, J., Huang, E., Gao, S., Li, H., Lu, J., Tian, K., Little, P. J., Shen, X., Xu, S., & Liu, P. (2014). Tanshinone IIA suppresses cholesterol accumulation in human macrophages: Role of heme oxygenase-1. Journal of Lipid Research, 55(2), 201–213. https://doi.org/10.1194/jlr.M040394
- Mohamed, R., Cao, Y., Afroz, R., Xu, S., Ta, H. T., Barras, M., Zheng, W., Little, P. J., & Kamato, D. (2020). ROS directly activates transforming growth factor beta type 1 receptor signalling in human vascular smooth muscle cells. Biochimica Et Biophysica Acta - General Subjects, 1864(1), 129463.
- Mohamed, R., Dayati, P., Mehr, R. N., Kamato, D., Seif, F., Babaahmadi-Rezaei, H., & Little, P. J. (2018). Transforming growth factor-beta1 mediated CHST11 and CHSY1 mRNA expression is ROS dependent in vascular smooth muscle cells. The Journal of Cell Communication and Signaling.
- Mohamed, R., Dayati, P., Mehr, R. N., Kamato, D., Seif, F., Babaahmadi-Rezaei, H., & Little, P. J. (2018). Transforming growth factor-beta1 mediated CHST11 and CHSY1 mRNA expression is ROS dependent in vascular smooth muscle cells. The Journal of Cell Communication and Signaling.
- Nigro, J., Osman, N., Dart, A. M., & Little, P. J. (2006). Insulin resistance and atherosclerosis. Endocrine Reviews, 27(3), 242–259. https://doi.org/10.1210/er.2005-0007
- Organization, W. H. (2017). Noncommunicable diseases: progress monitor 2017.
- Rostam, M. A., Kamato, D., Piva, T. J., Zheng, W., Little, P. J., & Osman, N. (2016). The role of specific Smad linker region phosphorylation in TGF-beta mediated expression of glycosaminoglycan synthesizing enzymes in vascular smooth muscle. Cellular Signalling, 28(8), 956–966.
- Rostam, M. A., Shajimoon, A., Kamato, D., Mitra, P., Piva, T. J., Getachew, R., Cao, Y., Zheng, W., Osman, N., & Little, P. J. (2018). Flavopiridol inhibits TGF-beta-stimulated biglycan synthesis by blocking linker region phosphorylation and nuclear translocation of Smad2. Journal of Pharmacology and Experimental Therapeutics, 365(1), 156–164.
- Salami, M., Moosavi-Movahedi, A. A., Moosavi-Movahedi, F., Ehsani, M. R., Yousefi, R., Farhadi, M., Niasari-Naslaji, A., Saboury, A. A., Chobert, J.-M., & Haertlé, T. (2011). Biological activity of camel milk casein following enzymatic digestion. Journal of Dairy Research, 78(4), 471–478. https://doi.org/10.1017/S0022029911000628
- Shah, N. P. (2000). Effects of milk-derived bioactives: An overview. British Journal of Nutrition, 84(S1), 3–10.
- Williams, K. J., & Tabas, I. (1995). The response-to-retention hypothesis of early atherogenesis. Arteriosclerosis, Thrombosis, and Vascular Biology, 15(5), 551–561. https://doi.org/10.1161/01.ATV.15.5.551
- Xu, S., Bai, P., Little, P. J., & Liu, P. (2014). Poly(ADP-ribose) polymerase 1 (PARP1) in atherosclerosis: From molecular mechanisms to therapeutic implications. Medicinal Research Reviews, 34(3), 644–675. https://doi.org/10.1002/med.21300
- Zhang, Y. J., Gan, R. Y., Li, S., Zhou, Y., Li, A. N., Xu, D. P., & Li, H. B. (2015). Antioxidant phytochemicals for the prevention and treatment of chronic diseases. Molecules, 20(12), 21138–21156. https://doi.org/10.3390/molecules201219753
