Extracellular vesicles in hypercholesterolemia-induced cardiotoxicity and helium-induced cardioprotection
Kovácsházi Csenger
Pharmaceutical Sciences
Dr. Zelkó Romána
NET Farmakológiai és Farmakoterápiás Intézet, Knoll (Issekutz) terem
2024-12-04 10:00:00
Modern Trends in Pharmaceutical Scientific Research
Dr. Antal István
Dr. Giricz Zoltán
Dr. Wiener Zoltán
Dr. Greskovics-Dobra Gabriella
Dr. Nagy György
Hriczóné Dr. Szebeni Beáta
Dr. Mihály Judit
CVDs are the leading cause of deaths worldwide(2), indicating an incomplete understanding of their pathomechanism. A major comorbidity of CVDs is metabolic diseases, including HC(2). EVs are nano-sized, cell-secreted membrane particles(23), involved in HC, CVDs and cardioprotective therapies(35–37,57). However, their role in cardiovascular homeostasis is yet unclear.
This thesis aims to elucidate the role of EVs in cardiac stress responses by examining the effect of a cardiotoxic condition, HC, and a cardioprotective intervention, HeC, on EVs. Specifically, the objectives are to: 1) analyze how HC modifies the metabolome of circulating EVs, 2) determine how HC regulates CM EV secretion, 3) investigate whether CM EVs in HC induce inflammation, and 4) examine how HeC modifies NRCF EV secretion.
pEVs were isolated from male Wistar Rats fed with hypercholesterolemic chow and their metabolome was analyzed using the Biocrates MxP Quant 500 kit. Furthermore, AC16 CMs were treated with Remembrane® HC supplement and sEVs were isolated from the cell culture supernatant. AC16 sEVs were quantitatively analyzed, used for THP-1-ASC-GFP monocyte cell treatment, and their proteome was measured with LC-MS/MS. In addition, HeC treatment was applied on CFs, mEVs were isolated, and HUVEC-TERT2 were treated with conditioned CF cell culture supernatant.
We found that HC reduces the amount of certain glycerophospholipids in pEVs. Furthermore, the metabolome of pEVs showed only minor correlation with plasma metabolome. HC treatment increased AC16 sEV secretion, however sEVs from neither experimental group activated monocytes. On the other hand, proteomics of AC16 sEVs revealed significant effects of HC, and certain proteins involved in in cardiac tissue remodeling found enriched. HeC had no major effect on CF mEV secretion, and supernatant transfer from HeC-treated CFs to HUVEC-TERT2 did not affect recipient cell function.
In conclusion, HC alters the composition and potentially the function of both circulating and CM-derived EVs. Furthermore, CF EVs do not play major role in HeC. Our results demonstrates that EVs are involved in the regulation of cardiac homeostasis. For complete understanding of these mechanisms, experiments with specific focus on subpopulations of EVs are needed.
