Plasma-derived extracellular vesicles from myocardial infarction patients inhibits tumor necrosis factor-alpha induced cardiac cell death

Avinash Khandagale; Bertil Lindahl; Sara Bergström Lind; Ganna Shevchenko; Agneta Siegbahn; Christina Christersson

doi:10.1016/j.retram.2021.103323

Plasma-derived extracellular vesicles from myocardial infarction patients inhibits tumor necrosis factor-alpha induced cardiac cell death

Curr Res Transl Med. 2022 May;70(2):103323. doi: 10.1016/j.retram.2021.103323. Epub 2021 Dec 31.

Authors

Avinash Khandagale¹, Bertil Lindahl², Sara Bergström Lind³, Ganna Shevchenko⁴, Agneta Siegbahn⁵, Christina Christersson²

Affiliations

¹ Department of Medical Sciences, Cardiology, Uppsala University, Uppsala, Sweden; Clinical Chemistry Uppsala University, Uppsala, Sweden. Electronic address: avinash.khandagale@medsci.uu.se.
² Department of Medical Sciences, Cardiology, Uppsala University, Uppsala, Sweden.
³ Department of Chemistry BMC, Analytic Chemistry, Uppsala University, Uppsala, Sweden; Faculty Offices, Office for Science and Technology, Uppsala University, Uppsala, Sweden.
⁴ Department of Chemistry BMC, Analytic Chemistry, Uppsala University, Uppsala, Sweden.
⁵ Clinical Chemistry Uppsala University, Uppsala, Sweden.

PMID: 34979484
DOI: 10.1016/j.retram.2021.103323

Abstract

Rationale: Extracellular vesicles (EVs) derived exogenously from pluripotent stem cells or endogenously from healthy human serum exert cardioprotective effects after injury. However role of endogenous EVs from myocardial infarction (MI) patients not well understood in this settings.

Methods and results: The EVs from plasma of MI patients with preserved or reduced left ventricular ejection fraction (LVEF) and healthy controls (HC) were purified and characterized by flow cytometry, mass spectrometry (MS) and transmission electron microscopy (TEM). HCM and human cardiac microvascular endothelial cells (hCMVECs), under individual culture or co-culture, were used to study functional effects of EVs upon TNFα stimulation. These effects of EVs on HCM and hCMVECs were observed using cell death assays, western blots and confocal microscopy. Higher concentrations of platelet-, leukocyte-, endothelial- and erythrocyte-derived EVs were found in MI patients, both with preserved and reduced LVEF, compared to HC, and MS data on MI EVs proteome displayed alteration in several proteins. MI EVs protected HCM and hCMVECs against staurosporine-induced apoptosis. Furthermore, MI EVs were observed to abrogate TNFα-triggered HCM and hCMVECs death under both individually cultured and co-cultured conditions. MI EVs failed to inhibit TNFα induced hCMVECs and HCM activation when cultured individually, however co-cultured hCMVECs with HCM supported MI EVs capacity to attenuate TNFα induced cells activation. MI CD41+ EVs but not HC EVs were found to be internalized by HCM directly or migrated through hCMVECs to HCM. MI EVs indirectly restores TNFα mediated drop in mitochondrial membrane potential.

Conclusions: Endogenous EVs from MI patients, regardless of severity of the MI exert cardioprotective potential upon TNFα-induced cell death. Patient-derived EVs needs to be further explored to elucidate their potential cardioprotective role during MI.

Keywords: Apoptosis; Cardiomyocytes; Extracellular vesicles; Myocardial infarction; Tumor necrosis factor alpha.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Apoptosis
Disease Models, Animal
Endothelial Cells
Extracellular Vesicles*
Humans
Myocardial Infarction* / metabolism
Myocardial Infarction* / pathology
Stroke Volume
Tumor Necrosis Factor-alpha / metabolism
Ventricular Function, Left

Substances

Tumor Necrosis Factor-alpha