MIR-128 TARGETING PPAR-γ IMPROVES VASCULAR REMODELING IN SPONTANEOUSLY HYPERTENSIVE RATS BY REGULATING THE TLR4/NFKB INFLAMMATORY PATHWAY
Discuss this preprint
Start a discussion What are Sciety discussions?Listed in
This article is not in any list yet, why not save it to one of your lists.Abstract
OBJECTIVE
This study aimed to explore the role and underlying mechanism of microRNA-128 (miR-128) in regulating vascular remodeling in spontaneously hypertensive rats (SHRs), focusing on its targeting of peroxisome proliferator-activated receptor γ (PPAR-γ) and modulation of the Toll-like receptor 4/nuclear factor-κB (TLR4/NF-κB) inflammatory pathway.
METHODS
All experimental procedures were approved by the Animal Care and Use Committee of Fujian Medical University. In vivo, ten-week-old male SHRs were randomly assigned to three groups: renal denervation (RDN, n=6), sacubitril/valsartan (Sac/Val, n=6), and Sham (n=6). Age-matched Wistar-Kyoto (WKY) rats served as normotensive controls (n=6).Eight weeks after intervention, mesenteric arteries were harvested for histological, functional, and molecular analyses. Serum miR-128 levels were measured by quantitative real-time polymerase chain reaction (qRT-PCR). The expression levels of key proteins in the vascular wall were assessed via immunofluorescence (IF), immunohistochemistry (IHC), and Western blotting (WB). Bioinformatics analysis and RNA sequencing (RNA-seq) were employed to identify core genes and signaling pathways associated with hypertension-induced pathological inflammation.
RESULTS
In vivo, in the SHR sham-operated group, elevated blood pressure, severe vascular remodeling, and impaired vasodilatory function were observed, accompanied by downregulated miR-128 expression and upregulated TLR4/NF-κB signaling activity (all p < 0.0001).RDN postoperative, miR-128 expression was significantly restored, which in turn inhibited the TLR4/NF-κB pathway, reduced the production of pro-inflammatory cytokines (including IL-1β, IL-6, and TNF-α), and ameliorated vascular dilation dysfunction in SHRs (all p < 0.0001). Mechanistically, miR-128 negatively regulated the TLR4/NF-κB signaling pathway while upregulating the expression of PPAR-γ (p < 0.05).
CONCLUSION
RDN not only exerts a hypotensive effect but also improves hypertensive vascular remodeling. miR-128 inhibits excessive inflammation in vascular smooth muscle cells and alleviates vascular remodeling in SHRs via the PPAR-γ/TLR4/NF-κB axis. These findings identify miR-128 as a potential therapeutic target for RDN in the treatment of hypertension, providing a novel regulatory strategy for the precision management of cardiovascular diseases.
