Effect of Lysyl Oxidase Inhibition on Angiotensin II-Induced Arterial Hypertension, Remodeling, and Stiffness

Eberson, Lance S.; Sanchez, Pablo; Majeed, Beenish; Tawinwung, Supannikar; Secomb, Timothy W.; Larson, Douglas F.

doi:10.1371/journal.pone.0124013

Cited by 39 publications

(31 citation statements)

References 39 publications

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“…Previous studies reported increased LOX mRNA or activity levels in some models of hypertension (19,43,48). We confirm these observations and demonstrate that the upregulation of vascular LOX protein levels observed in SHR and Ang II-infused mice relies, at least in part, on the hemodynamic effects induced by high blood pressure.…”

Section: Discussionsupporting

confidence: 89%

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

Martínez-Revelles

García-Redondo

Avendaño

et al. 2017

Antioxidants & Redox Signaling

105

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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.

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Section: Discussionsupporting

confidence: 89%

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

Martínez-Revelles

García-Redondo

Avendaño

et al. 2017

Antioxidants & Redox Signaling

105

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“…LOX has been shown to induce an age‐dependent disturbance of diastolic function and aggravates angiotensin II (Ang II)‐induced hypertrophy . In addition, inhibition of LOX by BAPN attenuated the Ang II‐induced arterial hypertension and adventitial thickness . Besides, BAPN attenuated volume overload‐induced increase in cardiac stress, levels of collagen I and III, and cardiac dysfunction in the heart failure model rats induced by volume overload following aortocaval fistula (ACF) .…”

Section: Discussionmentioning

confidence: 99%

Induction of LOX by TGF‐β1/Smad/AP‐1 signaling aggravates rat myocardial fibrosis and heart failure

Qin

Yao

et al. 2019

IUBMB Life

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This study aims to evaluate the efficacy of lysyl oxidase (LOX) inhibition in regulating rat myocardial fibrosis and chronic heart failure (CHF) and to validate the regulation of LOX by TGF-β1/Smad2/3 signaling in this process. A rat model of CHF was established by abdominal aortic coarctation. The renin-angiotensinaldosterone system (RAAS) indexes (PRA, ACE2, Ang II, and ALD), cardiac function indicators (LVEF, LVFS, SAP, DAP, and LVEDP), ventricular remodeling-and fibrosis-related indicators (hydroxyproline, collagen deposition, and MMP-2/9), and morphological changes of myocardial tissues were examined. Rat cardiac fibroblasts (RCFs) were used in vitro assays. CHF patients showed increased LOX activity, accompanied by activated RAAS and TGF-β1. Furthermore, inhibition of LOX by β-aminopropionitrile (BAPN) mitigated the RAAS activation and attenuated cardiac dysfunction, ventricular remodeling, myocardial fibrosis, and collagen deposition in CHF rats. Moreover, TGF-β1 signaling diminished the LOX inhibition-mediated antiheart failure effect. Further assays showed that TGF-β1/ Smad2/3 signaling increased expression of c-jun (AP-1 transcription factor subunit), which transcriptionally induced LOX expression. Additionally, BAPN abrogated the TGF-β1-mediated increase in cell proliferation and levels of MMP-2/9 and collagen I/III in RCFs. In conclusion, LOX can be induced by TGF-β1/Smad/AP-1 signaling and LOX inhibition attenuates rat myocardial fibrosis and CHF. K E Y W O R D S chronic heart failure, c-Jun, LOXSmadTGF-β1

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“…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).…”

Section: Discussionmentioning

confidence: 99%

“…These studies indicate an essential role of LOX in maintaining the tensile and elastic features of blood vessels. Studies of the role of LOX in hypertensive aortic stiffening, however, have produced inconsistent results (Chen et al., 2013; Eberson et al., 2015). …”

Section: Introductionmentioning

confidence: 99%

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

Hays

Zhou

et al. 2018

Aging Cell

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SummaryAortic stiffening is an independent risk factor that underlies cardiovascular morbidity in the elderly. We have previously shown that intrinsic mechanical properties of vascular smooth muscle cells (VSMCs) play a key role in aortic stiffening in both aging and hypertension. Here, we test the hypothesis that VSMCs also contribute to aortic stiffening through their extracellular effects. Aortic stiffening was confirmed in spontaneously hypertensive rats (SHRs) vs. Wistar‐Kyoto (WKY) rats in vivo by echocardiography and ex vivo by isometric force measurements in isolated de‐endothelized aortic vessel segments. Vascular smooth muscle cells were isolated from thoracic aorta and embedded in a collagen I matrix in an in vitro 3D model to form reconstituted vessels. Reconstituted vessel segments made with SHR VSMCs were significantly stiffer than vessels made with WKY VSMCs. SHR VSMCs in the reconstituted vessels exhibited different morphologies and diminished adaptability to stretch compared to WKY VSMCs, implying dual effects on both static and dynamic stiffness. SHR VSMCs increased the synthesis of collagen and induced collagen fibril disorganization in reconstituted vessels. Mechanistically, compared to WKY VSMCs, SHR VSMCs exhibited an increase in the levels of active integrin β1‐ and bone morphogenetic protein 1 (BMP1)‐mediated proteolytic cleavage of lysyl oxidase (LOX). These VSMC‐induced alterations in the SHR were attenuated by an inhibitor of serum response factor (SRF)/myocardin. Therefore, SHR VSMCs exhibit extracellular dysregulation through modulating integrin β1 and BMP1/LOX via SRF/myocardin signaling in aortic stiffening.

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Effect of Lysyl Oxidase Inhibition on Angiotensin II-Induced Arterial Hypertension, Remodeling, and Stiffness

Cited by 39 publications

References 39 publications

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

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

Induction of LOX by TGF‐β1/Smad/AP‐1 signaling aggravates rat myocardial fibrosis and heart failure

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

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