Regulation of Vascular Calcification by Reactive Oxygen Species

Abstract

Vascular calcification is the deposition of hydroxyapatite crystals in the medial or intimal layers of arteries that is usually associated with other pathological conditions including but not limited to chronic kidney disease, atherosclerosis and diabetes. Calcification is an active, cell-regulated process involving the phenotype transition of vascular smooth muscle cells (VSMCs) from contractile to osteoblast/chondrocyte-like cells. Diverse triggers and signal transduction pathways have been identified behind vascular calcification. In this review, we focus on the role of reactive oxygen species (ROS) in the osteochondrogenic phenotype switch of VSMCs and subsequent calcification. Vascular calcification is associated with elevated ROS production. Excessive ROS contribute to the activation of certain osteochondrogenic signal transduction pathways, thereby accelerating osteochondrogenic transdifferentiation of VSMCs. Inhibition of ROS production and ROS scavengers and activation of endogenous protective mechanisms are promising therapeutic approaches in the prevention of osteochondrogenic transdifferentiation of VSMCs and subsequent vascular calcification. The present review discusses the formation and actions of excess ROS in different experimental models of calcification, and the potential of ROS-lowering strategies in the prevention of this deleterious condition.

Heme-Mediated Activation of the Nrf2/HO-1 Axis Attenuates Calcification of Valve Interstitial Cells

“…Recent evidence has proven that NF-κB activation and the excessive production of ROS are important mediators of vascular calcification [ 17 , 43 , 44 , 45 , 46 , 47 ]. Based on these facts, one can assume that heme would trigger vascular calcification.…”

“…The elevation of reactive oxygen species (ROS) formation plays a role in both vascular and valve calcification [ 17 , 18 ]. Normally, ROS formation is counterbalanced by a complex antioxidant defense system.…”

Role of Uremic Toxins in Early Vascular Ageing and Calcification

“…Additional sources of superoxide anion in the vasculature are eNOS. Oxidative stress is one of the better studied mechanisms that contribute to the uremic phenotype and VC [ 65 , 66 ]. In this sense, increased expression of the Nox subunits p22phox and p47phox and downregulation of the antioxidant enzymes SOD1, SOD2, Gpx1, and PRDX-1 were reported in the aorta of rats with CKD [ 67 ].…”

“…All these conditions use ROS production as a common intermediate to induce osteoblast/chondrogenic trans-differentiation of VSMCs and VC via the activation of different downstream pathways. More particularly, ROS production from different stimuli can induce the activation and nuclear translocation of several transcription factors, such as NF-kB, hypoxia-inducible factor (HIF)-1α [ 77 ], B-catenin, and Msx2, activating transcription factor 4 (ATF4), and CCAAT-enhancer-binding protein homologous protein (CHOP), all of which initiate the transcription program that provokes the VSMC transition from a contractile to a synthetic, pro-calcifying phenotype [ 66 ]. The cytoprotective transcription Nrf2 play an important role in protection against oxidative stress and inflammation in CKD [ 78 ].…”

Microarray analysis of the time‑dependent expression profiles of long non‑coding RNAs in the progression of vein graft stenotic disease

“…Intimal hyperplasia and atherosclerosis are also considered to be primary causes of lumen remodeling of the graft, which are associated with the processes of leukocyte adhesion and vascular endothelial cells and VSMC proliferation (35). Several studies have implicated the production of reactive oxygen species in disease progression in grafts (39,40). There is increasing evidence to demonstrate a pivotal role of MAPK activation cascades in vascular restenosis, which contribute to proliferation of VSMCs and neointima formation via downstream proteins (41).…”