Lysyl Oxidase Induces Vascular Oxidative Stress and Contributes to Arterial Stiffness and Abnormal Elastin Structure in Hypertension: Role of p38MAPK

Abstract

Aims: Vascular stiffness, structural elastin abnormalities, and increased oxidative stress are hallmarks of hypertension. Lysyl oxidase (LOX) is an elastin crosslinking enzyme that produces H 2 O 2 as a by-product. We addressed the interplay between LOX, oxidative stress, vessel stiffness, and elastin. Results: Angiotensin II (Ang II)-infused hypertensive mice and spontaneously hypertensive rats (SHR) showed increased vascular LOX expression and stiffness and an abnormal elastin structure. Mice over-expressing LOX in vascular smooth muscle cells (TgLOX) exhibited similar mechanical and elastin alterations to those of hypertensive models. LOX inhibition with b-aminopropionitrile (BAPN) attenuated mechanical and elastin alterations in TgLOX mice, Ang II-infused mice, and SHR. Arteries from TgLOX mice, Ang II-infused mice, and/or SHR exhibited increased vascular H 2 O 2 and O 2 .-levels, NADPH oxidase activity, and/or mitochondrial dysfunction. BAPN prevented the higher oxidative stress in hypertensive models. Treatment of TgLOX and Ang II-infused mice and SHR with the mitochondrial-targeted superoxide dismutase mimetic mito-TEMPO, the antioxidant apocynin, or the H 2 O 2 scavenger polyethylene glycol-conjugated catalase (PEG-catalase) reduced oxidative stress, vascular stiffness, and elastin alterations. Vascular p38 mitogen-activated protein kinase (p38MAPK) activation was increased in Ang II-infused and TgLOX mice and this effect was prevented by BAPN, mito-TEMPO, or PEG-catalase. SB203580, the p38MAPK inhibitor, normalized vessel stiffness and elastin structure in TgLOX mice. Innovation: We identify LOX as a novel source of vascular reactive oxygen species and a new pathway involved in vascular stiffness and elastin remodeling in hypertension. Conclusion: LOX up-regulation is associated with enhanced oxidative stress that promotes p38MAPK activation, elastin structural alterations, and vascular stiffness. This pathway contributes to vascular abnormalities in hypertension. Antioxid. Redox Signal. 27, 379-397.

Angiotensin II Signal Transduction: An Update on Mechanisms of Physiology and Pathophysiology

“…The contribution of Lox to arterial stiffness is confirmed with smooth muscle specific Lox overexpressed mice, which show higher vascular stiffness, but normal blood pressure (656). ANG II further enhances vascular Lox expression, and BAPN reduces ANG II-induced arterial stiffness, oxidative stress, and p38 MAPK activation in mice (656).…”

Vascular smooth muscle cells direct extracellular dysregulation in aortic stiffening of hypertensive rats

“…For example, while it has been shown that the downregulation of LOX contributes to the aortic stiffening in an obesity mouse model (Chen et al., 2013), other studies have shown that inhibition of LOX attenuated the angiotensin II induced aortic stiffening (Eberson et al., 2015). In addition, as evidence showed that genetic deletion or functional deficiency of LOX causes aortic wall destruction and leads to aortic stiffening (Lee et al., 2016; Maki et al., 2002; Staiculescu et al., 2017), a smooth muscle cell‐specific overexpression of LOX in a mouse model has been shown to induces arterial stiffness (Martinez‐Revelles et al., 2017). Although the reasons for these inconsistencies are unclear, one potential explanation may arise from the distinct extracellular and intracellular effects of LOX.…”

“…Although the reasons for these inconsistencies are unclear, one potential explanation may arise from the distinct extracellular and intracellular effects of LOX. Although it has been widely accepted that mature active LOX functions in the extracellular cross‐linking of collagens and elastin, this active form of LOX has also been detected to be increased inside the VSMCs and is able to stimulate intracellular signaling pathways as detected in LOX transgenic mice (Martinez‐Revelles et al., 2017). In addition, it has been reported that LOX‐PP participates in the regulation of the focal adhesion kinase in cancer cells (Zhao et al., 2009), although its biological activity in VSMC remains to be identified.…”

Lysyl oxidase (LOX) limits VSMC proliferation and neointimal thickening through its extracellular enzymatic activity

“…We have previously shown the critical contribution of LOX to the control of endothelial homeostasis 16–19 and to the regulation of vascular remodeling by modulating cell proliferation, ECM calcification and ROS production 15,20,28 . Neointimal thickening induced by carotid artery injury was attenuated in a transgenic mouse model that specifically over-expresses LOX in VSMC, consistent with the lower proliferative rates exhibited by VSMC from these animals 20 .…”