Caffeine Inhibits Oxidative Stress- and Low Dose Endotoxemia-Induced Senescence—Role of Thioredoxin-1
Dennis Merk,
Jan Greulich,
Annika Vierkant,
Fiona Cox,
Olaf Eckermann,
Florian von Ameln,
Nadine Dyballa-Rukes,
Joachim Altschmied,
Niloofar Ale-Agha,
Philipp Jakobs,
Judith Haendeler
Affiliations
Dennis Merk
Cardiovascular Degeneration, Haendeler Group, Clinical Chemistry and Laboratory Diagnostics, Medical Faculty, University Hospital, Heinrich-Heine University Duesseldorf, 40225 Duesseldorf, Germany
Jan Greulich
Cardiovascular Degeneration, Altschmied Group, Clinical Chemistry and Laboratory Diagnostics, Medical Faculty, University Hospital, Heinrich-Heine University Duesseldorf, 40225 Duesseldorf, Germany
Annika Vierkant
Cardiovascular Degeneration, Altschmied Group, Clinical Chemistry and Laboratory Diagnostics, Medical Faculty, University Hospital, Heinrich-Heine University Duesseldorf, 40225 Duesseldorf, Germany
Fiona Cox
Cardiovascular Degeneration, Haendeler Group, Clinical Chemistry and Laboratory Diagnostics, Medical Faculty, University Hospital, Heinrich-Heine University Duesseldorf, 40225 Duesseldorf, Germany
Olaf Eckermann
Cardiovascular Degeneration, Haendeler Group, Clinical Chemistry and Laboratory Diagnostics, Medical Faculty, University Hospital, Heinrich-Heine University Duesseldorf, 40225 Duesseldorf, Germany
Florian von Ameln
Cardiovascular Degeneration, Altschmied Group, Clinical Chemistry and Laboratory Diagnostics, Medical Faculty, University Hospital, Heinrich-Heine University Duesseldorf, 40225 Duesseldorf, Germany
Nadine Dyballa-Rukes
Cardiovascular Degeneration, Haendeler Group, Clinical Chemistry and Laboratory Diagnostics, Medical Faculty, University Hospital, Heinrich-Heine University Duesseldorf, 40225 Duesseldorf, Germany
Joachim Altschmied
Cardiovascular Degeneration, Altschmied Group, Clinical Chemistry and Laboratory Diagnostics, Medical Faculty, University Hospital, Heinrich-Heine University Duesseldorf, 40225 Duesseldorf, Germany
Niloofar Ale-Agha
Cardiovascular Degeneration, Haendeler Group, Clinical Chemistry and Laboratory Diagnostics, Medical Faculty, University Hospital, Heinrich-Heine University Duesseldorf, 40225 Duesseldorf, Germany
Philipp Jakobs
Cardiovascular Degeneration, Haendeler Group, Clinical Chemistry and Laboratory Diagnostics, Medical Faculty, University Hospital, Heinrich-Heine University Duesseldorf, 40225 Duesseldorf, Germany
Judith Haendeler
Cardiovascular Degeneration, Haendeler Group, Clinical Chemistry and Laboratory Diagnostics, Medical Faculty, University Hospital, Heinrich-Heine University Duesseldorf, 40225 Duesseldorf, Germany
The maintenance of Thioredoxin-1 (Trx-1) levels, and thus of cellular redox homeostasis, is vital for endothelial cells (ECs) to prevent senescence induction. One hallmark of EC functionality, their migratory capacity, which depends on intact mitochondria, is reduced in senescence. Caffeine improves the migratory capacity and mitochondrial functionality of ECs. However, the impact of caffeine on EC senescence has never been investigated. Moreover, a high-fat diet, which can induce EC senescence, results in approximately 1 ng/mL lipopolysaccharide (LPS) in the blood. Therefore, we investigated if low dose endotoxemia induces EC senescence and concomitantly reduces Trx-1 levels, and if caffeine prevents or even reverses senescence. We show that caffeine precludes H2O2-triggered senescence induction by maintaining endothelial NO synthase (eNOS) levels and preventing the elevation of p21. Notably, 1 ng/mL LPS also increases p21 levels and reduces eNOS and Trx-1 amounts. These effects are completely blocked by co-treatment with caffeine. This prevention of senescence induction is similarly accomplished by the permanent expression of mitochondrial p27, a downstream effector of caffeine. Most importantly, after senescence induction by LPS, a single bolus of caffeine inhibits the increase in p21. This treatment also blocks Trx-1 degradation, suggesting that the reversion of senescence is intimately associated with a normalized redox balance.
