VPO1 Modulates Vascular Smooth Muscle Cell Phenotypic Switch by Activating Extracellular Signal‐regulated Kinase 1/2 (ERK 1/2) in Abdominal Aortic Aneurysms

Abstract

BackgroundHydrogen peroxide (H2O2) is a critical molecular signal in the development of abdominal aortic aneurysm (AAA) formation. Vascular peroxidase 1 (VPO1) catalyzes the production of hypochlorous acid (HOCl) from H2O2 and significantly enhances oxidative stress. The switch from a contractile phenotype to a synthetic one in vascular smooth muscle cells (VSMCs) is driven by reactive oxygen species and is recognized as an early and important event in AAA formation. This study aims to determine if VPO1 plays a critical role in the development of AAA by regulating VSMC phenotypic switch.Methods and Results VPO1 is upregulated in human and elastase‐induced mouse aneurysmal tissues compared with healthy control tissues. Additionally, KLF4, a nuclear transcriptional factor, is upregulated in aneurysmatic tissues along with a concomitant downregulation of differentiated smooth muscle cell markers and an increase of synthetic phenotypic markers, indicating VSMC phenotypic switch in these diseased tissues. In cultured VSMCs from rat abdominal aorta, H2O2 treatment significantly increases VPO1 expression and HOCl levels as well as VSMC phenotypic switch. In support of these findings, depletion of VPO1 significantly attenuates the effects of H2O2 and HOCl treatment. Furthermore, HOCl treatment promotes VSMC phenotypic switch and ERK1/2 phosphorylation. Pretreatment with U0126 (a specific inhibitor of ERK1/2) significantly attenuates HOCl‐induced VSMC phenotypic switch.ConclusionsOur results demonstrate that VPO1 modulates VSMC phenotypic switch through the H2O2/VPO1/HOCl/ERK1/2 signaling pathway and plays a key role in the development of AAA. Our findings also implicate VPO1 as a novel signaling node that mediates VSMC phenotypic switch and plays a key role in the development of AAA.Clinical Trial Registration URL: http://www.chictr.org.cn. Unique identifier: ChiCTR1800016922.

Zinc interference with Cd‐induced hormetic effect in differentiated Caco‐2 cells: Evidence for inhibition downstream ERK activation

“…Cd, which binds to intracellular SH‐groups or may favor Fenton reaction by increasing free Fe 2+ , may indirectly induce oxidative stress, at least redox imbalance, and a positive correlation between ERK1/2 activation and pro‐oxidant conditions (related to H 2 O 2 ) have been shown in many studies . Our data show higher levels of Cd‐induced ERK1/2 phosphorylation in the presence of 3 mM BSO but lower levels when the cells were coincubated with Cd and 1 mM NAC (Figure ).…”

Vascular Smooth Muscle FTO Promotes Aortic Dissecting Aneurysms via m6A Modification of Klf5

“…Since GSK-3β has been demonstrated to directly phosphorylate KLF5 at S303 and then targets it for ubiquitination and degradation (43), suggesting that FTO upregulates Klf5 expression at protein level via inactivation of GSK-3β inhibits its phosphorylation and degradation. Additionally, previous reports show that PI3K/AKT signaling pathway mediates FTO-induced the energy metabolism of breast cancer cell (44), and proliferation-related ERK signaling pathway is activated heavily in aneurysms (45), however, in this study, we found that overexpression of FTO has little effects on these two signaling pathways in VSMCs. These findings indicate that FTO correlates with the distinct signaling pathways in the different cell contexts and particular pathways to exert corresponding functions.…”

TGF-β mediates aortic smooth muscle cell senescence in Marfan syndrome

“…Consistent with that idea, alteration of the VSMC phenotype reportedly contributes to aortic aneurysm formation or dissection in MFS [1, 18]. It has been reported that VPO1 promotes VSMC phenotypic switching through activation of the HOCl/ERK1/2 signaling pathway with consequent development of aortic aneurysm [19]. The XBP1u-FoxO4-myocardin axis is essential for maintaining the VSMC phenotype and blocking signaling leading to VSMC phenotypic transition [20].…”