HSP27 combines with anti-HSP27 IgG antibodies to form immune complexes that dock at the hepatocyte cell membrane, engage the receptor TLR4, activate the NF-kB pathway and upregulate the expression of the LDL-R (independent of SREBP2). Plasma LDL cholesterol and PCSK9 levels fall because of the increased clearance by the more abundant LDL-Rs.
Inflammation biomarkers are markedly reduced in: – blood (serum amyloid A levels drop >70%) – liver (cytokines: IL-1beta, TNF-alpha) – plaque (fewer macrophages & cholesterol crystals)
Research on women’s heart & brain health is gaining momentum!
Heart disease and stroke are the #1 cause of premature death for women, but two-thirds of patient-related research involves men. Similarly, there are lost opportunities if basic research focuses only on male cells or male animal models. The Heart & Stroke Foundation of Canada is making significant changes to address this gap. For more information, click on the full report: “A Fighting Chance“
Exciting research from the O’Brien Lab strives to develop a vaccine to prevent and treat Hardening of the arteries in post-menopausal women
HSP27 (short for Heat Shock Protein 27) is a protein (substance) that is naturally made by your body, and was discovered as a ‘protector’ against inflammation and hardening of the arteries (‘atherosclerosis’). Women have higher levels of HSP27 – at least until menopause – when levels decline. This is because the hormone estrogen (made by a woman’s ovaries) promote the production of HSP27. However, after menopause the levels of estrogen and HSP27 decline. Interestingly, there are antibodies to HSP27 that are naturally present, and ‘stick to’ HSP27 and help make it ‘work better’. This has lead to exciting new HSP27 vaccination experiments that show promise in preventing or treating atherosclerosis. Whether HSP27 will have other beneficial effects on the health of post-menopausal women is now an active area of research.
Stay tuned for updates from our March 2020 presentation at the Keystone Symposium entitled “Transforming Vaccinology” (Florence, IT), co-sponsored by the Bill and Melinda Gates Foundation. Our presentation entitled “HSP27 Vaccination Reduces Cholesterol and Atherogenesis” highlights how HSP27 Vaccination may lead to increased expression of the liver receptor (LDLR) that takes cholesterol out of the blood, as well as reduce the abundance of another factor (PCSK9) that raises cholesterol levels.
Very rewarding international experience, working with my colleagues (standing in photo below) to mentor the world’s future leaders in Women’s Cardiovacular Health research @LibinInstitute #LibinITS
Featured speakers included:
Dr. Sharon Mulvagh, Co-Director of the Women’s Heart Health Clinic at the Maritime Heart Center at Dalhousie University, and Professor Emeritus, Mayo Clinic, MN @HeartDocSharon
Dr. Jeanine Roeters van Lennep from Erasmus University, telling us about @ZonMw, the Dutch Research Funding agency that helps improve health and healthcare in the Netherlands.
Trainees from the Netherlands
This international trainee symposium brought together bright young trainees who will be our future independent investigators. While many were from Canada, the attendance of the Dutch trainees (photo below) was impressive and helped make this meeting extremely successful.
Thanks to the many who participated or made this meeting possible, including:
Dr. George Lambros (photo above, front row on left) and Canadian Pacific Railway for their sponsorship and continued commitment with “CP Has Heart” campaign @CPhasHeart
Anne Simard, Chief Mission and Research Officer @HeartandStroke Foundation of Canada
Dr. Sofia Ahmed (photo above, front row on right), Dr. Paul Fedak (Director of the Libin Institute) and the many colleagues & members of the Libin Institute’s #CV&Me initiative.
October 2019 BBA General Subjects publication from the O’Brien lab advances the knowledge base for understanding the interaction of anti-HSP27 antibodies with HSP27. Such HSP27 immune complexes are involved in extra-cellular cellular signalling that results in the reduction in atherogenesis, cholesterol levels and inflammation.
“Biophysical analyses and functional implications of the interaction between heat shock protein 27 and antibodies to HSP27” by: Michael H. Chiu, Chunhua Shi, Matthew Rosin, Zarah Batulan, Edward R. O’Brien
The structure of HSP27 was modeled using the PHYRE Protein Fold Recognition Server, intensive mode, generating a 3D structure in which 174 aa (85% of the total 205 aa sequence) were modeled at >90% accuracy.
Grateful to be celebrated with my peers at the Libin Cardiovascular Institute of Alberta’s 6th Annual Gala. The community came together again to recognize and foster excellence in cardiovascular care and research.
Thanks for the excellent feedback and questions regarding my presentation at ESC 2019 in Paris (Sept. 3rd), entitled “HSP25 Immunotherapy Post-Menopause is Superior to Estradiol in Targeting Atherosclerosis”. There is a real opportunity for the development of HSP27 immune-facilitated therapeutics for the reduction of both cholesterol and inflammation – particularly for post-menopausal women who are at increased risk of cardiovascular events. Stay tuned for new developments in our HSP27 vaccination pipeline.
To learn more about heart disease in women, watch the following short Womdocumentary exploring the deadly disparity between male and female heart disease, via healthcare professionals, researchers, patients, & families
For the 1/3 of women who are menopausal, the risk of heart disease is much higher compared to pre-menopause. Unfortunately less is known about heart disease in women and there are no sex-specific therapies. Dr Ed O’Brien is a cardiologist and his research laboratory discovered a protein that acts as a “foot soldier” for estrogen. Estrogen levels plummet with menopause when ovarian function ceases – typically between 45 and 55 years – and are thought to be “protective” against the development of heart disease.
While estrogen “replacement” therapies for post-menopausal women are used to releive some symptoms of menopause (e.g., hot flashes) there are concerns about their safety. Indeed, a recent meta-analysis from Oxford University, published in the Lancet on August 29, 2019, suggests that the risk of breast cancer with hormone replacement therapy during menopause is higher than previously understood.
Hence, there is a need to look for new alternatives to HRT for post-menopausal women – and the O’Brien lab has developed a new immunotherapy involving Heat Shock Protein 27 (HSP27) that may be very important in reducing cholesterol levels and hardening of the arteries (“atherosclerosis”).
In a Late Breaking Basic and Translational Science presentation at the European Society of Cardiology Congress in Paris, Dr. O’Brien reported that vaccination with HSP27 is superior to Estrogen therapy in a mouse model of menopause (that involves surgical removal of the ovaries).
Briefly, Estrogen was found to dramatically increase levels of PCSK9 – a negative regulator of cholesterol metabolism. In contrast, HSP27 (or the mouse equivalent, HSP25) had no effect on PCSK9 expression levels, but could neutralize the bad effect of Estrogens on PCSK9.
Conversely, HSP25 increased the expression levels of the receptor (LDL-R) that removes low density lipoprotein (“bad”) cholesterol from the circulation, and reduces the development of hardening of the arteries.
Taken together, these data provide a new opportunity for the development of a therapy for post-menopausal atherosclerosis that involves a simple vaccination technique. In separate studies, this HSP27 vaccination strategy also reduces inflammation, and is effective in male as well as female mice. Studies are ongoing, and are aimed at translating these research developments to the clinic.