By Lucy Piper, medwireNews Reporter
medwireNews: Caffeine may protect against endothelial dysfunction in patients with systemic lupus erythematosus (SLE), suggest Italian researchers.
They found that daily caffeine intake positively correlated with the percentage of circulating endothelial progenitor cells (EPCs) in patients with SLE, and in vitro caffeine treatment improved EPC survival.
EPCs are “essential for vascular damage repair and a decrease in their number is associated with subclinical atherosclerosis”, which is “widely documented in SLE patients”, Fulvia Ceccarelli (Sapienza University of Rome) and colleagues explain in Rheumatology.
They hypothesize that the positive effect of caffeine is “linked to a direct action on EPC survival and vitality through the inhibition of apoptosis and the promotion of autophagy.”
A total of 31 patients with SLE, aged a median of 43 years, were enrolled in the study and had their caffeine intake monitored for 7 days using a food frequency questionnaire that identified all the main sources of caffeine intake.
The median intake of caffeine was 166 mg/day, primarily from coffee, and the median percentage of EPC cells was 0.03, with an interquartile range of 0.04. The researchers note that patients with a history for neuropsychiatric lupus had a significantly lower percentage of EPCs than those without, as did patients who were receiving treatment with glucocorticoids versus those who were not, at a median of 0.01 versus 0.04 and 0.03 versus 0.04, respectively.
In vitro experiments where EPCs from six healthy donors were co-cultured with caffeine at 0.5 mM and 1.0 mM, with and without SLE sera showed that EPCs treated with SLE sera and caffeine had better morphology and a significantly greater number had colony forming units compared with those incubated with SLE sera without caffeine, at a mean of 15 versus 5.
The EPC colonies that formed with SLE sera were “poorly organized” compared with those that were not and “the addition of caffeine was able to restore the colony structure”, the team reports.
To investigate the effects of caffeine on EPCs further, Ceccarelli and co-workers evaluated autophagy in the EPCS of peripheral blood mononuclear cells from six healthy donors that had been co-cultured with SLE sera with and without caffeine.
They found that LC3-II levels, a marker of autophagic activity, were significantly reduced in the absence of caffeine, but the levels increased after the addition of caffeine restoring them to healthy levels.
This was also the case for the apoptotic marker p62, levels of which increased in EPCs treated with SLE sera but decreased to normal levels with the addition of caffeine.
These findings remained consistent when lysosomal inhibitors were added and when the percentage of annexin V and PI staining for apoptosis was evaluated by flow cytometry and the anti-apoptotic molecule Bcl-2 was assessed via Western blot.
Moreover, they believe this “could be mediated by SIRT3/AMPK stimulating autophagy,” finding that co-culturing EPCs from healthy donors with sera from SLE patients significantly increased adenosine A2A receptor levels and decreased SIRT3 and phosphorylated AMP-activated protein kinase (AMPK)/AMPK levels. When treated with caffeine, A2AR levels significantly decreased leading to a significant increase in SIRT3 and subsequently AMPK phosphorylation.
The team explains that SIRT3, a mitochondrial nicotinomide adenine dinucleotide(+)-dependent deacetylase, “has emerged as an important player in [cardiovascular disease], influencing endothelial dysfunction, atherosclerosis, oxidative stress and inflammation.” And AMPK is a downstream target of SIRT3 “and a known positive regulator of autophagy.”
They note that their data “are in line with previous results highlighting the positive AMPK-inducing effect of caffeine on EPCs.”
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Rheumatology 2024; doi:10.1093/rheumatology/keae453