Inhibition of biliverdin reductase diminished the protective activity of bilirubin and biliverdin against oxidative stress-induced injury in human vascular endothelium

Sharma, Kuldeepak (author), Zajc, Irena (author), Albreht, Alen (author), Žiberna, Lovro (author)

Endothelial dysfunction, a key factor in cardiovascular diseases, is further aggravated by oxidative stress. Biliverdin (BV) and bilirubin (BR) are potent antioxidants that protect endothelial cells, with biliverdin reductase (BVR) converting BV to BR to maintain redox balance. This study explored BVR's role in mediating these protective effects under normoxic and hypoxia-reoxygenation conditions. Pharmacological inhibition of BVR reduced the protective effects of BV and BR, as evidenced by decreased cell viability, cellular antioxidant activity, and intracellular bilirubin levels. Activation of ERK1/2 reduced BVR's protective function, while its inhibition enhanced it. Additionally, disruption of the BVR-ERK interaction further modulated these effects, highlighting the BVR-ERK1/2 interaction sites as potential therapeutic targets for oxidative stress-induced endothelial dysfunction.

• Language: English
• Keywords: antioxidant, bilirubin, biliverdin, biliverdin reductase, human endothelium, oxidative stress
• Work type: Article
• Typology: 1.01 - Original Scientific Article
• Organization: FFA - Faculty of Pharmacy; MF - Faculty of Medicine
• Publication status: Published
• Publication version: Version of Record
• Year: 2024
• Number of pages: Str. 627-645
• Numbering: Vol. 71, no. 4
• PID: 20.500.12556/RUL-166308
• UDC: 612.015+611.018.74
• ISSN on article: 1580-3155
• DOI: 10.17344/acsi.2024.8964
• COBISS.SI-ID: 220977155
• Publication date in RUL: 07.01.2025

Record is a part of a journal

• Title: Acta chimica slovenica
• Shortened title: Acta chim. slov.
• Publisher: Slovensko kemijsko društvo, = Slovenian Chemical Society
• ISSN: 1580-3155
• COBISS.SI-ID: 21870085

Licences

• License: CC BY 4.0, Creative Commons Attribution 4.0 International
• Link: http://creativecommons.org/licenses/by/4.0/
• Description: This is the standard Creative Commons license that gives others maximum freedom to do what they want with the work as long as they credit the author.

Secondary language

• Language: Slovenian

Abstract

Endotelijska disfunkcija je pomemben dejavnik tveganja za razvoj srčno-žilnih bolezni, njeno stanje pa dodatno poslabša oksidativni stres. Biliverdin (BV) in bilirubin (BR) sta močna antioksidanta, ki ščitita endotelijske celice, pri čemer encim biliverdin reduktaza (BVR) pretvarja BV v BR za vzdrževanje redoks ravnovesja. Naša raziskava je preučevala vlogo BVR pri posredovanju teh zaščitnih učinkov v normoksičnih pogojih in pogojih hipoksije-reoksigenacije. Farmakološka inhibicija BVR je zmanjšala zaščitne učinke BV in BR, kar se kaže v zmanjšani viabilnosti celic, znotrajcelični antioksidativni sposobnosti in nižjih ravneh znotrajceličnega bilirubina. Aktivacija ERK1/2 je zmanjšala zaščitno funkcijo BVR, medtem ko jo je njena inhibicija povečala. Poleg tega je zaviranje interakcije med BVR in ERK dodatno vplivalo na delovanje BV in BR, kar kaže, da bi lahko vezavna mesta interakcije BVR-ERK1/2 predstavljala potencialne terapevtske tarče za zdravljenje endotelijske disfunkcije, povzročene z oksidativnim stresom.

• Keywords: antioksidant, bilirubin, biliverdin, biliverdin reduktaza, človeški endotelij, oksidativni stres, endotelij