PRMT5 critically mediates TMAO-induced inflammatory response in vascular smooth muscle cells

Abstract

A high plasma level of the choline-derived metabolite trimethylamine N-oxide (TMAO) is closely related to the development of cardiovascular disease. However, the underlying mechanism remains unclear. In the present study, we demonstrated that a positive correlation of protein arginine methyltransferase 5 (PRMT5) expression and TMAO-induced vascular inflammation, with upregulated vascular cell adhesion molecule-1 (VCAM-1) expression in primary rat and human vascular smooth muscle cells (VSMC) in vitro. Knockdown of PRMT5 suppressed VCAM-1 expression and the adhesion of primary bone marrow-derived macrophages to TMAO-stimulated VSMC. VSMC-specific PRMT5 knockout inhibited vascular inflammation with decreased expression of VCAM-1 in mice. We further identified that PRMT5 promoted VCAM-1 expression via symmetrical demethylation of Nuclear factor-κB p65 on arginine 30 (R30). Finally, we found that TMAO markedly induced the expression of nicotinamide adenine dinucleotide phosphate oxidase 4 (Nox4) and production of reactive oxygen species, which contributed to PRMT5 expression and subsequent VCAM-1 expression. Collectively, our data provide novel evidence to establish a Nox4-PRMT5-VCAM-1 in mediating TMAO-induced VSMC inflammation. PRMT5 may be a potential target for the treatment of TMAO-induced vascular diseases.

Protein Arginine Methyltransferase 5 Contributes to Paclitaxel-Induced Neuropathic Pain by Activating Transient Receptor Potential Vanilloid 1 Epigenetic Modification in Dorsal Root Ganglion

“…PTX-Mediated Upregulation of PRMT5 Requires Increased NOX4 in DRG Neurons NOX4 contributes to PRMT5 expression in inflammatory disease. 18 Due to the fact that PTX can also affect NOX4 expression, 13 as well as the fact that the abovementioned results demonstrated that PRMT5 in the DRG modulates the progression of PTX-induced neuropathic pain, we further proposed that PTX-mediated upregulation of PRMT5 may require increased NOX4. Western blot analysis demonstrated that PTX increased the abundance of NOX4 in DRGs at days 7, 14, and 21 after treatment (Figure 3A).…”

Gut microbiota in hypertensive patients with versus without obstructive sleep apnea

“… 18 , 35 Lactobacillus is also positively associated with trimethylamine N ‐oxide (TMAO) levels. 36 The TMAO has been associated with the risk of CVDs such as vascular inflammation, 37 atherosclerosis, and heart failure. 38 Moreover, TMAO promotes angiotensin II‐induced vasoconstriction and aggravates angiotensin II‐induced hypertension.…”

Gut Molecules in Cardiometabolic Diseases: The Mechanisms behind the Story

“…The authors of this study demonstrated that oxidative stress activation is required for TMAO-induced inflammation, and it involves molecular mechanisms, such as the suppression of the AMPK/SIRT1 signaling pathway [ 120 ]. In an in vitro study, TMAO induced the inflammatory reaction and the synthesis of ROS and favored the expression of adhesion molecules in vascular smooth muscle cells via nicotinamide adenine dinucleotide phosphate oxidase 4 (Nox4)/protein arginine methyltransferase 5 (PRMT5)/NF-κB p65/VCAM-1 signaling cascade [ 121 ]. Supplementary studies showed that TMAO could stimulate MAPK/ERK/NF-κB cascade [ 122 ] and NLRP3 activation through the SORT3-SOD2-mitochondrial ROS signaling pathway [ 123 ] to promote vascular inflammation as an atherogenic condition.…”