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MicroRNA?24 attenuates diabetic vascular remodeling by suppressing the NLRP3/caspase?1/IL?1? signaling pathway.

ABSTRACT: Vascular remodeling plays an important role in the pathogenesis of diabetic cardiovascular complications. Previous published research has indicated that microRNA?24 (miR?24) is involved in diabetic vascular remodeling, but the underlying molecular mechanisms have yet to be fully elucidated. The aim of the present study was to investigate whether adenovirus?mediated miR?24 overexpression can suppress the NOD?like receptor family pyrin domain?containing 3 (NLRP3)?related inflammatory signaling pathway and attenuate diabetic vascular remodeling. The carotid arteries of diabetic rats were harvested and prepared for analysis. Reverse transcription?quantitative PCR and western blotting assays were used to detect the expressions of related mRNAs and proteins. Morphological examinations, including hematoxylin and eosin, immunohistochemical and Masson's trichrome staining, were also performed. The results of the present study demonstrated that miR?24 upregulation suppressed neointimal hyperplasia and accelerated reendothelialization in the injured arteries, lowered the expression of NLRP3, apoptosis?associated speck?like protein, caspase?1, proliferating cell nuclear antigen, CD45, interleukin (IL)?1?, IL?18 and tumor necrosis factor??, and increased the expression of CD31, smooth muscle (SM) ??actin and SM?myosin heavy chain. These data indicated that miR?24 overexpression can attenuate vascular remodeling in a diabetic rat model through suppressing the NLRP3/caspase?1/IL?1? signaling pathway.

SUBMITTER: Fan Z

PROVIDER: S-EPMC7138286 | biostudies-literature | 2020 Mar

REPOSITORIES: biostudies-literature

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MicroRNA‑24 attenuates diabetic vascular remodeling by suppressing the NLRP3/caspase‑1/IL‑1β signaling pathway.

Fan Zhixing Z Yang Jian J Yang Chaojun C Zhang Jing J Cai Wanying W Huang Congxin C

International journal of molecular medicine 20200309 5

Vascular remodeling plays an important role in the pathogenesis of diabetic cardiovascular complications. Previous published research has indicated that microRNA‑24 (miR‑24) is involved in diabetic vascular remodeling, but the underlying molecular mechanisms have yet to be fully elucidated. The aim of the present study was to investigate whether adenovirus‑mediated miR‑24 overexpression can suppress the NOD‑like receptor family pyrin domain‑containing 3 (NLRP3)‑related inflammatory signaling pat ...[more]

PMID: 32323758

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Project description:Diabetes mellitus is an established risk factor associated with bisphosphonate-related osteonecrosis of the jaw (BRONJ). Sustained activation of Nod-like receptor (NLR) family, pyrin domain-containing protein 3 (NLRP3) inflammasome contributes to the persistent inflammation and impaired cutaneous wound healing in diabetic mice and human. We have recently demonstrated a compelling linkage between M1 macrophages and BRONJ conditions in both murine and human diseases. The aim of this study was to determine whether NLRP3 inflammasome activation is involved in BRONJ development in diabetic mice. We showed an increased incidence of delayed oral wound healing and bone necrosis of extraction sockets in db/db mice compared with those in nondiabetic db/+ controls, which correlated with an elevated expression of NLRP3, caspase-1, and IL-1? in macrophages residing at local wounds. Constitutively, bone marrow-derived macrophages from db/db mice (db/db BMDMs) secrete a relatively higher level of IL-1? than those from db/+ mice (db/+ BMDMs). Upon stimulation by NLRP3 activators, the secretion of IL-1? by db/db BMDMs was 1.77-fold higher than that by db/+ BMDMs (p?<?0.001). Systemic treatment of mice with zoledronate (Zol), a nitrogen-containing bisphosphonate, resulted in a 1.86- and 1.63-fold increase in NLRP3/caspase-1-dependent IL-1? secretion by db/+ and db/db BMDMs, respectively, compared with BMDMs derived from nontreated mice (p?<?0.001). Importantly, systemic administration of pharmacological inhibitors of NLRP3 activation improved oral wound healing and suppressed BRONJ formation in db/db mice. Mechanistically, we showed that supplementation with intermediate metabolites of the mevalonate pathway, inhibitors of caspase-1 and NLRP3 activation, an antagonist for P2X7 R, or a scavenger of reactive oxygen species (ROS), robustly abolished Zol-enhanced IL-1? release from macrophages in response to NLRP3 activation (p?<?0.001). Our findings suggest that diabetes-associated chronic inflammatory response may have contributed to impaired socket wound healing and rendered oral wound susceptible to the development of BRONJ via NLRP3 activation in macrophages.

Dataset Information

MicroRNA?24 attenuates diabetic vascular remodeling by suppressing the NLRP3/caspase?1/IL?1? signaling pathway.

Publications

MicroRNA‑24 attenuates diabetic vascular remodeling by suppressing the NLRP3/caspase‑1/IL‑1β signaling pathway.

Similar Datasets

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