Altered endothelial dysfunction-related miRs in plasma from ME/CFS patients

Abstract

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a complex disease characterized by unexplained debilitating fatigue. Although the etiology is unknown, evidence supports immunological abnormalities, such as persistent inflammation and immune-cell activation, in a subset of patients. Since the interplay between inflammation and vascular alterations is well-established in other diseases, endothelial dysfunction has emerged as another player in ME/CFS pathogenesis. Endothelial nitric oxide synthase (eNOS) generates nitric oxide (NO) that maintains endothelial homeostasis. eNOS is activated by silent information regulator 1 (Sirt1), an anti-inflammatory protein. Despite its relevance, no study has addressed the Sirt1/eNOS axis in ME/CFS. The interest in circulating microRNAs (miRs) as potential biomarkers in ME/CFS has increased in recent years. Accordingly, we analyze a set of miRs reported to modulate the Sirt1/eNOS axis using plasma from ME/CFS patients. Our results show that miR-21, miR-34a, miR-92a, miR-126, and miR-200c are jointly increased in ME/CFS patients compared to healthy controls. A similar finding was obtained when analyzing public miR data on peripheral blood mononuclear cells. Bioinformatics analysis shows that endothelial function-related signaling pathways are associated with these miRs, including oxidative stress and oxygen regulation. Interestingly, histone deacetylase 1, a protein responsible for epigenetic regulations, represented the most relevant node within the network. In conclusion, our study provides a basis to find endothelial dysfunction-related biomarkers and explore novel targets in ME/CFS.

Perspective: Drawing on Findings From Critical Illness to Explain Myalgic Encephalomyelitis/Chronic Fatigue Syndrome

“…This is consistent with recent hypotheses describing vasoconstriction in muscle and brain as a principal element of ME/CFS (42)(43)(44)(45)(46), and findings of cerebral hypoperfusion (47)(48)(49) and intracranial hypertension (50) in ME/CFS patients. It is also consistent with studies that have shown that endothelial function is impaired in ME/CFS (51,52), both in large vessels and in the microcirculation (53, 54)-associated with redox imbalance (51). Finally, it is consistent with a new hypothesis for ME/CFS which suggests that endothelial senescence underpins ME/CFS by disrupting the intestinal barriers and BBBs (55), as well as with suggestions that leakage from dysfunctional blood vessels could explain many of the symptoms in ME/CFS (56).…”

An attempt to explain the neurological symptoms of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome

“…Meanwhile more evidence for endothelial dysfunction has accumulated. Altered endothelial dysfunction-related microRNAs were found in plasma from ME/CFS patients recently [ 5 ]. In Covid-19 infection the endothelium is severely affected and the disturbance seems to persist in post-Covid Syndrome (PCS) [ 8 , 12 , 20 , 23 , 34 ].…”

Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS): An Overview

“…Silent information regulator 1 (Sirt1) reduces inflammation and oxidative stress and increases the production of nitric oxide by activating the endothelial nitric oxide synthase. MiR-21, miR-34a, miR-92a, miR-126, and miR-200c regulate endothelial function via the Sirt1/eNOS axis but it is necessary to further explore how this regulation occurs and its effectors [ 169 ].…”