Elevated Uric Acid Levels Promote Vascular Smooth Muscle Cells (VSMC) Proliferation via an Nod-Like Receptor Protein 3 (NLRP3)-Inflammasome-Dependent Mechanism

Abstract

BackgroundHyperuricemia has a pathogenic role in the development of hypertension and other cardiovascular diseases (CVD). Uric acid has been reported to activate Nod-like receptor protein 3 (NLRP3)-inflammasome and alter vascular smooth muscle cells (VSMC). However, the potential mechanisms underlying this association are still not understood. The aim of this study was to investigate the role and potential mechanisms of uric acid in proliferation of VSMC.Material/MethodsCell Counting Kit-8 (CCK-8) proliferation assay and colony formation assay were performed to determine the proliferative ability of VSMC under uric acid stimulation. Immunofluorescence microscopy was carried out to determine the expression of Alpha-smooth muscle actin (α-SMA). In addition, real-time PCR and Western blot were used to detect the expression of NLRP3-inflammasome, and ELISA was performed to measure the levels of IL-18 and IL-1β.ResultsThe results showed that uric acid increases the proliferation of VSMC and induces α-SMA accumulation. We also found that uric acid increases the level of NLRP3 and induces NLRP3-inflammasome activation. The expressions of uric acid-induced inflammatory markers IL-1β and IL-18 were decreased by the inhibitor MCC950.ConclusionsOur findings revealed that uric acid induces inflammation through NLRP3-inflammasome-mediated VSMC proliferation. NLRP3 may be a new therapeutic target for hypertension.

Uric Acid and Cardiovascular Disease: An Update From Molecular Mechanism to Clinical Perspective

“…Studies by Wang et al report that UA can activate nod-like receptor protein 3 (NLRP3) inflammasomes and damage mitochondria, resulting in cellular damage of H9c2 cells ( Wang et al, 2018 ). In addition, several studies also show that UA activates the NLRP3 inflammasome and induces interleukin-1β (IL-1β) release in a variety of cells, including monocytes, macrophages, vascular smooth muscle cells, and endothelial cells ( Martinon et al, 2006 ; Matias et al, 2015 ; Alberts et al, 2019 ; Kim et al, 2019 ; Li et al, 2019 ; Yin et al, 2019 ). The molecular mechanism of UA-induced NLRP3/IL-1 β activation is through NF-κB activation and mitochondrial ROS (mROS) ( Figure 2 ).…”

Gender-Specific Association of Serum Uric Acid and Pulmonary Function: Data from the Korea National Health and Nutrition Examination Survey

“…Furthermore, hyperuricemia is related to hypertension, coronary heart disease, stroke, diabetes, obesity, and metabolic syndrome [1][2][3][4][5]. The mechanistic role of UA in several comorbidities suggested that UA stimulates vascular smooth muscle proliferation and oxidative stress [6]. Hyperuricemia is associated with endothelial dysfunction by inducing inhibition of nitric oxide production [7].…”

Identification of Novel Long Noncoding RNAs and Their Role in Abdominal Aortic Aneurysm

“…KEGG pathway analysis showed that phagosomes are the most enriched pathways in upregulated genes, and drug metabolism-cytochrome P450 is the most enriched pathway in downregulated genes. Among the significantly enriched pathways, the NOD-like receptor (NLR) pathway, cell adhesion molecule (CAM), and the NF-kappa B (NF- κ B) signaling pathway are potentially closely related to AAA pathogenesis [ 23 – 25 ]. It was considered that these lncRNAs might participate in the biological process of SMAD protein signal transduction and immune response in AAA progression via mediating the above significantly enriched pathways.…”