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Endothelial cell (EC) dysfunction is prevalent in individuals with insulin resistance and diabetes, characterized by diminished phosphorylation of endothelial nitric oxide synthase (p-eNOS) and reduced nitric oxide (NO) production in the endothelium. Despite its common occurrence, the fundamental mechanism underlying EC dysfunction remains incompletely understood. Dysregulation of microRNAs (miRNAs) has been implicated in EC biology and metabolic disorders, yet studies exploring the functional relevance of these miRNAs are limited. In this investigation, venous EC samples were collected from patients with type 2 diabetes mellitus (T2DM) and non-diabetic (ND) individuals (n=20/group). Subsequent miRNA sequencing revealed 37 upregulated and 21 downregulated miRNAs (P1). Notably, increased expression of miR-409-3p (L2FC>2) emerged as a potential target associated with EC dysfunction. Validation experiments conducted on human aortic EC (HAEC) exposed to high glucose palmitate (HGPAL) confirmed a significant upregulation of miR-409-3p (P2). In the same experimental setup, insulin-induced p-eNOS was decreased following HGPAL treatment. However, inhibition of miR-409-3p restored p-eNOS levels (18% to 20%), surpassing controls (21%), by enhancing insulin action in EC. Further investigations involving knockdown and overexpression of miR-409-3p demonstrated its negative regulation of p-eNOS in EC. The molecular mechanism uncovered indicates that miR-409-3p modulates p-eNOS signaling through JNK activity, as confirmed by fluorescence microscopy in patient ECs and by western blot in HAECs. In summary, this study identifies an altered miRNA repertoire in EC derived from T2DM patients, suggesting miR-409-3p as a key player in regulating insulin resistance and EC function. Ongoing study looks is delving into the transcriptional targets of miR-409-3p and their functional implications in both T2DM patients and cultured EC. These findings will shed light on the intricate interplay between miRNAs and EC dysfunction, offering potential avenues for therapeutic exploration in the realm of diabetes-associated vascular complications.
Rizvi et al. (2024) studied this question.