Author + information
- Received July 18, 2018
- Revision received March 11, 2019
- Accepted March 13, 2019
- Published online August 26, 2019.
- Mizanur Rahman, PhDa,
- Johnny Steuer, MD, PhDb,
- Peter Gillgren, MD, PhDb,
- Ákos Végvári, PhDc,
- Anquan Liu, MD, PhDa and
- Johan Frostegård, MD, PhDa,∗ ()
- aInstitute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden
- bSection of Vascular Surgery, Department of Surgery, Södersjukhuset, Institution of Clinical Science and Education, Karolinska Institutet, Stockholm, Sweden
- cDivision of Chemistry I, Department of Medical Biochemistry and Biophysics, Biomedicum, Karolinska Institutet, Stockholm, Sweden
- ↵∗Address for correspondence:
Dr. Johan Frostegård, Unit of Immunology and Chronic Disease, Institute of Environmental Medicine, Karolinska Institutet, Nobels väg 13, 171 65 Stockholm, Sweden.
• MDA conjugated with HSA activates T cells from human atherosclerotic plaques through a direct mechanism.
• MDA-HSA also induces maturation and activation of human dendritic cells, which in turn promote activation of autologous T cells from the same donor's plaques, although this effect appears somewhat weaker than the direct activation.
• M1 polarization of macrophages, potentially an atherogenic effect, were also induced by MDA-HSA.
• Heat shock protein 60 was induced in T cells by MDA-HSA, is atherogenic, and could promote dendritic cell/T cell activation.
• Two peptide modifications of serum albumin in atherosclerotic patients’ HSA were similar to those generated by treatment of HSA with MDA in vitro.
Human dendritic cells were differentiated from blood monocytes and treated with malondialdehyde (MDA) conjugated with human serum albumin (HSA). Autologous T cells from human plaques or blood were co-cultured with the pre-treated dendritic cells or treated directly. MDA modifications were studied by mass spectrometry. MDA-HSA induced a pro-inflammatory DC-mediated T-cell activation and also a strong direct effect on T cells, inhibited by an inhibitor of oxidative stress and antibodies against MDA. Atherogenic heat shock protein-60 was strongly induced in T cells activated by MDA-HSA. Two peptide modifications in atherosclerotic patients' HSA were similar to those present in in vitro MDA-modified HSA.
This research was financed by the Swedish Heart-Lung Foundation, the Swedish Research Council, the King Gustav V 80th Birthday Fund, the Swedish Association Against Rheumatism, Vinnova, and Torsten Söderberg’s Foundation. These funders played no role in study design, data collection, and analysis; the decision to publish; or preparation of the manuscript. Dr. Frostegård is named as inventor on patents and patent applications related to phosphorylcholine, but also for malondialdehyde, which is a topic in this paper. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.
All authors attest they are in compliance with human studies committees and animal welfare regulations of the author’s institutions and Food and Drug Administration guidelines, including patient consent where appropriate. For more information, visit the JACC: Basic to Translational Science author instructions page.
- Received July 18, 2018.
- Revision received March 11, 2019.
- Accepted March 13, 2019.
- 2019 The Authors