The role of p66ShcA-TLR9 signaling in myocardial remodeling and innate immune responses
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AbstractIschemic heart disease and myocardial infarction increase the risk of fatal heart failure via adverse myocardial remodeling. Cardiac cell death during myocardial infarction results in release of pro-inflammatory factors like mitochondrial DNA (mtDNA), leading to innate immunity activation, sterile inflammation, and damage amplification. mtDNA triggers inflammation via Toll-like receptor 9 (TLR9). The p66ShcA is a stress-sensitive protein involved in the regulation of the immune system. This work investigated whether TLR9 and p66ShcA regulate remodeling post-infarction. Cell cultures, p66ShcA knockout mice, an in vivo mouse model of myocardial infarction and tissue samples from patients with ischemic heart disease were used. Cardiac p66ShcA and TLR9 were upregulated, while the p66ShcA knockout mice had improved myocardial healing post-infarction. The p66ShcA was a positive upstream regulator of TLR9 signaling. mtDNA was released into the bloodstream of patients undergoing coronary bypass surgery. The findings suggest that p66ShcA-TLR9 signaling and mtDNA leakage are involved in sterile inflammation and myocardial remodeling post-infarction.
List of papers
|Paper I: The p66ShcA adaptor protein regulates healing after myocardial infarction. Anton Baysa, Julia Sagave, Andrea Carpi, Tatiana Zaglia, Marika Campesan, Christen Dahl, Dusan Bilbija, Maria Troitskaya, Lars Gullestad, Marco Giorgio, Marco Mongillo, Fabio Di Lisa, Jarle Vaage, Guro Valen. Basic Research in Cardiology, 2015 Mar;110(2):13. doi: 10.1007/s00395-015-0470-0. The article is included in the thesis. Also available at: https://doi.org/10.1007/s00395-015-0470-0|
|Paper II: Toll-like receptor 9 signaling after myocardial infarction: Role of p66shcA adaptor protein. Anton Baysa, Azzam Maghazachim, Kristin Larsen Sand, Marika Campesan, Tania Zaglia, Marco Mongillo, Marco Giorgio, Fabio Di Lisa, Lars H. Mariero, PhD Jarle Vaage, Guro Valen, Kåre-Olav Stensløkken. Manuscript, to be submitted. To be published. The paper is not available in DUO awaiting publishing.|
|Paper III: Release of mitochondrial and nuclear DNA during on-pump heart surgery: Kinetics and relation to extracellular vesicles. Anton Baysa, Anton Fedorov, Kirill Kondratov, Arno Ruusalepp, Sarkis Minasian, Michael Galagudza, Maxim Popov, Dmitry Kurapeev, Alexey Yakovlev, Guro Valen, Anna Kostareva, Jarle Vaage, Kåre-Olav Stensløkken. J Cardiovasc Translational Res. 2018, Dec 12. doi: 10.1007/s12265-018-9848-3. The article is included in the thesis. Also available at: https://doi.org/10.1007/s12265-018-9848-3|