Cardiac and vascular phenotypes in the apolipoprotein E-deficient mouse

Vasquez, Elisardo C.; Peotta, Veronica A.; Gava, Agata L.; Pereira, Thiago de Melo Costa; Meyrelles, Silvana S.

doi:10.1186/1423-0127-19-22

Cited by 77 publications

(81 citation statements)

References 91 publications

(142 reference statements)

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“…We tested this hypothesis in atherosclerosis-prone apoE Ϫ/Ϫ type 1 diabetic mice. As previously shown, these mice develop LV contractile dysfunction, atherosclerosis, and nephropathy (40,42). We show that recombinant human (rh)NRG-1, in the absence of effects on glycemia and cholesterolemia, attenuates development of LV dysfunction, atherosclerotic plaque formation, and nephropathy.…”

mentioning

confidence: 62%

Neuregulin-1 attenuates development of nephropathy in a type 1 diabetes mouse model with high cardiovascular risk

Vandekerckhove

Vermeulen

Liu

et al. 2016

American Journal of Physiology-Endocrinology and Metabolism

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Vandekerckhove L, Vermeulen Z, Liu ZZ, Boimvaser S, Patzak A, Segers VF, De Keulenaer GW. Neuregulin-1 attenuates development of nephropathy in a type 1 diabetes mouse model with high cardiovascular risk. Am J Physiol Endocrinol Metab 310: E495-E504, 2016. First published January 19, 2016 doi:10.1152/ajpendo.00432.2015 is an endothelium-derived growth factor with cardioprotective and antiatherosclerotic properties and is currently being tested in clinical trials as a treatment for systolic heart failure. In clinical practice, heart failure often coexists with renal failure, sharing an overlapping pathophysiological background. In this study, we hypothesized that NRG-1 might protect against cardiomyopathy, atherosclerosis, and nephropathy within one disease process. We tested this hypothesis in a hypercholesterolemic apolipoprotein E-deficient (apoE Ϫ/Ϫ ) type 1 diabetes mouse model prone to the development of cardiomyopathy, atherosclerosis, and nephropathy and compared the effects of NRG-1 with insulin. Upon onset of hyperglycemia induced by streptozotocin, apoE Ϫ/Ϫ mice were treated with vehicle, insulin, or recombinant human (rh)NRG-1 for 14 wk and were compared with nondiabetic apoE Ϫ/Ϫ littermates. Vehicle-treated diabetic apoE Ϫ/Ϫ mice developed left ventricular (LV) dilatation and dysfunction, dense atherosclerotic plaques, and signs of nephropathy. Nephropathy was characterized by abnormalities including hyperfiltration, albuminuria, increased urinary neutrophil gelatinase-associated lipocalin (NGAL), upregulation of renal fibrotic markers, and glomerulosclerosis. rh-NRG-1 treatment induced systemic activation of ErbB2 and ErbB4 receptors in both heart and kidneys and prevented LV dilatation, improved LV contractile function, and reduced atherosclerotic plaque size. rhNRG-1 also significantly reduced albuminuria, NGALuria, glomerular fibrosis, and expression of fibrotic markers. Regarding the renal effects of rhNRG-1, further analysis showed that rhNRG-1 inhibited collagen synthesis of glomerular mesangial cells in vitro but did not affect AngII-induced vasoconstriction of glomerular arterioles. In conclusion, systemic administration of rhNRG-1 in hypercholesterolemic type 1 diabetic mice simultaneously protects against complications in the heart, arteries and kidneys.

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mentioning

confidence: 62%

Neuregulin-1 attenuates development of nephropathy in a type 1 diabetes mouse model with high cardiovascular risk

Vandekerckhove

Vermeulen

Liu

et al. 2016

American Journal of Physiology-Endocrinology and Metabolism

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“…Enhanced levels of oxygen radicals, which characterize a state of oxidative stress, have been described in clinical and preclinical studies in many cardiovascular diseases, including diabetes, hypertension, and atherosclerosis (Minuz et al, 2002;Porto et al, 2011;Silva et al, 2012;Vasquez et al, 2012;Luévano-Contreras et al, 2013). Indeed, an excess of either molecular oxygen or chemical derivatives of oxygen (Kodja and Harrison, 1999) may be a common underlying pathogenic mechanism in these diseases.…”

Section: Oxidative Stressmentioning

confidence: 99%

Renovascular Hypertension Leads to DNA Damage and Apoptosis in Bone Marrow Cells

Campagnaro

Tonini

Doche

et al. 2013

DNA and Cell Biology

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Angiotensin II (Ang II), which plays a pivotal role in the pathophysiology of the two-kidney, one-clip (2K1C) Goldblatt hypertension, has been associated with augmented generation of reactive oxygen species (ROS) in some cells and tissues. In the present study, we evaluated the influence of 2K1C hypertension on oxidative stress, DNA fragmentation, and apoptosis of bone marrow (BM) cells. Two weeks after the renal artery clipping or Sham operation, flow cytometry analysis showed a higher production of superoxide anions (approximately sixfold) and hydrogen peroxide (approximately twofold) in 2K1C hypertensive than in Sham normotensive mice. 2K1C mice also showed an augmented DNA fragmentation (54%) and apoptotic cells (21%). Our data show that the 2K1C renovascular hypertension is characterized by an increased production of ROS, DNA damage, and apoptosis of BM, which is a fundamental source of the cells involved in tissue repair.

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“…In the last three decades, genetically modified mice have been extensively used as models for understanding the causes and mechanisms involved in human diseases and have contributed to the consolidation of translational research in cardiovascular and metabolic disorders [5, 7, 8, 13, 14]. Among the available models, the apoE -/- mouse was the first and most widely used for this purpose.…”

Section: Introductionmentioning

confidence: 99%

“…Among the available models, the apoE -/- mouse was the first and most widely used for this purpose. Loss of apoE gene expression in this animal compromises the hepatic clearance of VLDL and LDL, leading to spontaneous hypercholesterolemia [1, 3, 7]. Moreover, apoE -/- mice exhibit impaired vasodilation and enhanced vasoconstriction responsiveness, which are hallmarks of endothelial dysfunction in this experimental model and in atherosclerotic humans [4, 5, 7].…”

Section: Introductionmentioning

confidence: 99%

“…Loss of apoE gene expression in this animal compromises the hepatic clearance of VLDL and LDL, leading to spontaneous hypercholesterolemia [1, 3, 7]. Moreover, apoE -/- mice exhibit impaired vasodilation and enhanced vasoconstriction responsiveness, which are hallmarks of endothelial dysfunction in this experimental model and in atherosclerotic humans [4, 5, 7]. Previous studies have contributed to understanding of the mechanisms of impaired relaxation of both resistance and conductance vasodilation in the apoE -/- mouse [7, 15].…”

Section: Introductionmentioning

confidence: 99%

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Sildenafil (Viagra®) Prevents Cox-1/ TXA2 Pathway-Mediated Vascular Hypercontractility in ApoE-/- Mice

Leal

Dias

Porto³

et al. 2017

Cell Physiol Biochem

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Background/Aims: The atherosclerotic apolipoprotein E-deficient (apoE^-/-) mouse exhibits impaired vasodilation and enhanced vasoconstriction responsiveness. The objectives of this study were: a) to determine the relative contribution of cyclooxygenases (Cox-1 and Cox-2), thromboxane A2 (TXA2) and endothelin-1 (ET-1) to enhancing vascular hyperresponsiveness in this model of atherosclerosis and b) to investigate the beneficial effects of the phosphodiesterase 5 inhibitor sildenafil on this endothelial dysfunction. Methods: Adult male apoE^-/- mice were treated with sildenafil (40 mg/kg/day, for 3 weeks) and compared with non-treated ApoE^-/- and wild-type mice. The beneficial effects of sildenafil on vascular contractile response to phenylephrine (PE) in aortic rings were evaluated before and after incubation with Cox-1 (SC-560) or Cox-2 (NS-398) inhibitors or the TP antagonist SQ-29548, and on contractile responsiveness to ET-1. Results: ApoE^-/- mice exhibited enhanced vasoconstriction to PE (R_max ∼35%, p<0.01), which was prevented by treatment with sildenafil. The enhanced PE-induced contractions were abolished by both Cox-1 inhibition and TP antagonist, but were not modified by Cox-2 inhibition. Aortic rings from ApoE^-/- mice also exhibited enhanced contractions to ET-1 (R_max ∼30%, p<0.01), which were attenuated in sildenafil-treated ApoE^-/- mice. In addition, we observed augmented levels of vascular proinflammatory cytokines in ApoE^-/- mice, which were partially corrected by treatment with sildenafil (IL-6, IL-10/IL-6 ratio and MCP-1). Conclusion: The present data show that the Cox-1/TXA2 pathway prevails over the Cox-2 isoform in the mediation of vascular hypercontractility observed in apoE^-/-mice. The results also show a beneficial effect of sildenafil on this endothelial dysfunction and on the proinflammatory cytokines in atherosclerotic animals, opening new perspectives for the treatment of other endothelium-related cardiovascular abnormalities.

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Cardiac and vascular phenotypes in the apolipoprotein E-deficient mouse

Cited by 77 publications

References 91 publications

Neuregulin-1 attenuates development of nephropathy in a type 1 diabetes mouse model with high cardiovascular risk

Neuregulin-1 attenuates development of nephropathy in a type 1 diabetes mouse model with high cardiovascular risk

Renovascular Hypertension Leads to DNA Damage and Apoptosis in Bone Marrow Cells

Sildenafil (Viagra®) Prevents Cox-1/ TXA2 Pathway-Mediated Vascular Hypercontractility in ApoE-/- Mice

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