The lysyl oxidase inhibitor (β-aminopropionitrile) reduces leptin profibrotic effects and ameliorates cardiovascular remodeling in diet-induced obesity in rats

Martínez‐Martínez, Ernesto; Rodrı́guez, Cristina; Galán, María; Miana, María; Jurado-López, Raquel; Bartolomé, María Visitación; Luaces, María; Islas, Fabián; Martínez-González, José; López‐Andrés, Natalia; Cachofeiro, Victoria

doi:10.1016/j.yjmcc.2016.01.012

Cited by 54 publications

(35 citation statements)

References 45 publications

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“…Increased expression of TGFβ and CTGF has been implicated in the increase in vascular collagen and fibronectin synthesis and accompanying increases in fibrosis/stiffness in rodent models of aging, diet-induced obesity, and hypertension. 27,53–56 To this point, we found that exercise was associated with a reduction in aortic tissue fibronectin and collagen-1 (stiff collagen form) in the adventitia and media, respectively. However, despite this reduction in expression of TGFβ, CTGF, fibronectin and collagen-1, we did not detect significant changes in periaortic fibrosis, as assessed with PRS staining, which may explain the lack of exercise effects on aortic PWV, an in vivo marker of aortic stiffness.…”

Section: Discussionmentioning

confidence: 84%

Regular Exercise Reduces Endothelial Cortical Stiffness in Western Diet–Fed Female Mice

et al. 2016

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We recently showed that Western diet (WD)-induced obesity and insulin resistance promotes endothelial cortical stiffness in young female mice. Herein, we tested the hypothesis that regular aerobic exercise would attenuate the development of endothelial and whole artery stiffness in female WD-fed mice. Four-week old C57BL/6 mice were randomized into sedentary (i.e., caged confined, n=6) or regular exercise (i.e., access to running wheels, n=7) conditions for 16 weeks. Exercise training improved glucose tolerance in the absence of changes in body weight and body composition. Compared to sedentary mice, exercise-trained mice exhibited reduced endothelial cortical stiffness in aortic explants (sedentary: 11.9±1.7 kPa vs. exercise: 5.5±1.0 kPa; p<0.05), as assessed by atomic force microscopy. This effect of exercise was not accompanied by changes in aortic pulse wave velocity (p>0.05), an in vivo measure of aortic stiffness. In comparison, exercise reduced femoral artery stiffness in isolated pressurized arteries and led to an increase in femoral internal artery diameter and wall cross-sectional area (p<0.05), indicative of outward hypertrophic remodeling. These effects of exercise were associated with an increase in femoral artery elastin content and increased number of fenestrae in the internal elastic lamina (p<0.05). Collectively, these data demonstrate for the first time that the aortic endothelium is highly plastic and thus amenable to reductions in stiffness with regular aerobic exercise in the absence of changes in in vivo whole aortic stiffness. Comparatively, the same level of exercise caused de-stiffening effects in peripheral muscular arteries such as the femoral artery that perfuse the working limbs.

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Section: Discussionmentioning

confidence: 84%

Regular Exercise Reduces Endothelial Cortical Stiffness in Western Diet–Fed Female Mice

et al. 2016

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“…Thus, an increased expression and activity of LOX has been demonstrated in the myocardium of patients with heart failure, as well as with dilated cardiomyopathy, which correlated with increased collagen content and collagen cross-linking [27,28]. Although experimental rodent models of several cardiac disorders have enabled the assessment of the role of LOX activity in the progression of cardiac dysfunction and adverse ECM alterations, further studies are needed to identify accurately injurious stimuli, as well as cellular mechanisms responsible for the increased LOX expression and LOX-dependent damage in the heart [29,30].…”

Section: Discussionmentioning

confidence: 99%

Secreted Phospholipase A2-IIA Modulates Transdifferentiation of Cardiac Fibroblast through EGFR Transactivation: An Inflammation–Fibrosis Link

Martín

Gutiérrez

Cordova

et al. 2020

Cells

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Secreted phospholipase A 2 -IIA (sPLA 2 -IIA) is a pro-inflammatory protein associated with cardiovascular disorders, whose functions and underlying mechanisms in cardiac remodelling are still under investigation. We herein study the role of sPLA 2 -IIA in cardiac fibroblast (CFs)-to-myofibroblast differentiation and fibrosis, two major features involved in cardiac remodelling, and also explore potential mechanisms involved. In a mice model of dilated cardiomyopathy (DCM) after autoimmune myocarditis, serum and cardiac sPLA 2 -IIA protein expression were found to be increased, together with elevated cardiac levels of the cross-linking enzyme lysyl oxidase (LOX) and reactive oxygen species (ROS) accumulation. Exogenous sPLA 2 -IIA treatment induced proliferation and differentiation of adult rat CFs. Molecular studies demonstrated that sPLA 2 -IIA promoted Src phosphorylation, shedding of the membrane-anchored heparin-binding EGF-like growth factor (HB-EGF) ectodomain and EGFR phosphorylation, which triggered phosphorylation of ERK, P70S6K and rS6. This was also accompanied by an up-regulated expression of the bone morphogenic protein (BMP)-1, LOX and collagen I. ROS accumulation were also found to be increased in sPLA 2 -IIA-treated CFs. The presence of inhibitors of the Src/ADAMs-dependent HB-EGF shedding/EGFR pathway abolished the CF phenotype induced by sPLA 2 -IIA. In conclusion, sPLA 2 -IIA may promote myofibroblast differentiation through its ability to modulate EGFR transactivation and signalling as key mechanisms that underlie its biological and pro-fibrotic effects.

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“…Cardiac fibroblasts were isolated from a pool of 5 adult mouse hearts (11). Cells were used between passages 2 and 4.…”

Section: Cell Culture Studiesmentioning

confidence: 99%

“…Evidence from experimental and clinical studies suggest that LOX deregulation could underlie the development of cardiovascular diseases (10). We and others have reported increased cardiac LOX expression/activity in animal models of infarct and in the hypertrophic heart from hypertensive animals and rats fed a high-fat diet (7,11). Similarly, in humans, LOX is highly expressed in the fibrotic myocardium of patients with hypertensive heart disease and chronic HF (12,13).…”

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confidence: 93%

Lysyl oxidase overexpression accelerates cardiac remodeling and aggravates angiotensin II–induced hypertrophy

et al. 2017

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Lysyl oxidase (LOX) controls matrix remodeling, a key process that underlies cardiovascular diseases and heart failure; however, a lack of suitable animal models has limited our knowledge with regard to the contribution of LOX to cardiac dysfunction. Here, we assessed the impact of LOX overexpression on ventricular function and cardiac hypertrophy in a transgenic LOX (TgLOX) mouse model with a strong cardiac expression of human LOX. TgLOX mice exhibited high expression of the transgene in cardiomyocytes and cardiofibroblasts, which are associated with enhanced LOX activity and HO production and with cardiofibroblast reprogramming. LOX overexpression promoted an age-associated concentric remodeling of the left ventricle and impaired diastolic function. Furthermore, LOX transgenesis aggravated angiotensin II (Ang II)-induced cardiac hypertrophy and dysfunction, which triggered a greater fibrotic response that was characterized by stronger collagen deposition and cross-linking and high expression of fibrotic markers. In addition, LOX transgenesis increased the Ang II-induced myocardial inflammatory infiltrate, exacerbated expression of proinflammatory markers, and decreased that of cardioprotective factors. Mechanistically, LOX overexpression enhanced oxidative stress and potentiated the Ang II-mediated cardiac activation of p38 MAPK while reducing AMPK activation. Our findings suggest that LOX induces an age-dependent disturbance of diastolic function and aggravates Ang II-induced hypertrophy, which provides novel insights into the role of LOX in cardiac performance.-Galán, M., Varona, S., Guadall, A., Orriols, M., Navas, M., Aguiló, S., de Diego, A., Navarro, M. A., García-Dorado, D., Rodríguez-Sinovas, A., Martínez-González, J., Rodriguez, C. Lysyl oxidase overexpression accelerates cardiac remodeling and aggravates angiotensin II-induced hypertrophy.

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The lysyl oxidase inhibitor (β-aminopropionitrile) reduces leptin profibrotic effects and ameliorates cardiovascular remodeling in diet-induced obesity in rats

Cited by 54 publications

References 45 publications

Regular Exercise Reduces Endothelial Cortical Stiffness in Western Diet–Fed Female Mice

Regular Exercise Reduces Endothelial Cortical Stiffness in Western Diet–Fed Female Mice

Secreted Phospholipase A2-IIA Modulates Transdifferentiation of Cardiac Fibroblast through EGFR Transactivation: An Inflammation–Fibrosis Link

Lysyl oxidase overexpression accelerates cardiac remodeling and aggravates angiotensin II–induced hypertrophy

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