Heat Shock Protein 27 Immune Complex Upregulates LDLR Expression Thereby Reducing Plasma Cholesterol and Atherogenesis

Chen, Y.-X.; Shi, C.; Deng, J.; Diao, C.; Maarouf, N.; Rosin, M.; Shrivastava, V.; Hu, A.; Bharadwa, S.; Adijiang, A.; Ulke-Lemee, A.; Gwilym, B. L.; Hellmich, A.; Malozzi, C.; Batulan, Z.; Dean, J. L. E.; Ramirez, F. D.; Liu, J.; Gerthoffer, W. T.; O'Brien, E. R.

doi:10.1101/2020.05.21.102350

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bioRxiv · 10.1101/2020.05.21.102350

Heat Shock Protein 27 Immune Complex Upregulates LDLR Expression Thereby Reducing Plasma Cholesterol and Atherogenesis

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Abstract

Elevated Heat Shock Protein 27 levels predict relative freedom from cardiovascular events. In ApoE-/- mice HSP27 over-expression or twice daily subcutaneous injections reduce blood and plaque cholesterol levels, inflammation and atherogenesis. While natural antibodies to HSP27 are present in human blood their role is unknown. Here, we show that blood levels of both HSP27 and anti-HSP27 IgG antibodies are elevated in healthy controls compared to patients with cardiovascular disease. ApoE-/- mice vaccinated with recombinant HSP25 (murine ortholog) develop elevated anti-HSP25 IgG antibodies and reduced levels of cholesterol, inflammation and atherosclerosis. The effects on cholesterol metabolism were divergent: increased hepatic LDLR expression and reduced plasma PCSK9 levels. In vitro, a polyclonal anti-HSP27 IgG antibody combined with rHSP27 to upregulate hepatocyte LDLR expression via an NF-kB-dependent pathway that is independent of SREBP2 expression and intracellular cholesterol levels. HSP27 immunotherapy represents a novel means of lowering not only cholesterol but also PCSK9.Competing Interest StatementEOB and YXC are inventors on US patents 8343915B2 and 8343916B2 and EOB, CS and YXC are inventors on US patent application PCT/CA2016/051018, all pertaining to HSP27 diagnostics / therapeutics. EOB is the Scientific Co-Founder of Pemi31 Therapeutics Inc., a startup company that controls the aforementioned intellectual property. EOB, CS and YXC have equity interests in Pemi31 Therapeutics Inc.View Full Text

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Chen, Y.-X., Shi, C., Deng, J., Diao, C., Maarouf, N., Rosin, M., Shrivastava, V., Hu, A., Bharadwa, S., Adijiang, A., Ulke-Lemee, A., Gwilym, B. L., Hellmich, A., Malozzi, C., Batulan, Z., Dean, J. L. E., Ramirez, F. D., Liu, J., Gerthoffer, W. T., O'Brien, E. R.. 2020-05-25. Heat Shock Protein 27 Immune Complex Upregulates LDLR Expression Thereby Reducing Plasma Cholesterol and Atherogenesis. https://doi.org/10.1101/2020.05.21.102350

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