Sildenafil ameliorates oxidative stress and DNA damage in the stenotic kidneys in mice with renovascular hypertension

Dias, Ananda T.; Rodrigues, Bianca P; Porto, Marcella L.; Gava, Agata L.; Balarini, Camille M.; Freitas, Flávia Vitorino; Palomino, Zaira; Casarini, Dulce Elena; Campagnaro, Bianca Prandi; Pereira, Thiago de Melo Costa; Meyrelles, Silvana S.; Vasquez, Elisardo C.

doi:10.1186/1479-5876-12-35

Cited by 44 publications

(61 citation statements)

References 77 publications

(121 reference statements)

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“…This led us to propose that the reduction of pro-inflammatory mediators by sildenafil might be justified by an increase in cGMP. This possibility is supported by previous findings in other experimental models demonstrating that intracellular cGMP diminishes cytokine production and oxidative stress, thereby modulating the inflammatory response [74-76]. Therefore, it seems reasonable to consider that the correction of the enhanced contractile responsiveness promoted by sildenafil in aortic rings from apoE -/- mice could act, at least in part, via its antioxidant properties and indirect interaction with pro-inflammatory mediators, highlighting the benefits of the pleiotropic effects of sildenafil, as observed in other experimental models [4, 22].…”

Section: Discussionsupporting

confidence: 77%

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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Section: Discussionsupporting

confidence: 77%

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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“…The close relationship between inflammation and oxidative damage [6, 15, 22, 63] is supported by previous studies from our group demonstrating that virtually all cells from classical target organs of cardiovascular diseases are affected by ROS overproduction [7, 15, 20–23, 64, 65], mainly by the NADPH oxidases, which also are the main sources of ROS in phagocytic cells [66]. The present findings support the idea that the deleterious effects of ROS are not restricted to hypercholesterolemia and that they may be enhanced by aging, can occur in classical target tissue (e.g.…”

Section: Discussionsupporting

confidence: 63%

Increased ROS production and DNA damage in monocytes are biomarkers of aging and atherosclerosis

et al. 2018

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BackgroundNew evidence demonstrates that aging and dyslipidemia are closely associated with oxidative stress, DNA damage and apoptosis in some cells and extravascular tissues. However, in monocytes, which are naturally involved in progression and/or resolution of plaque in atherosclerosis, this concurrence has not yet been fully investigated. In this study, we evaluated the influence of aging and hypercholesterolemia on serum pro-inflammatory cytokines, oxidative stress, DNA damage and apoptosis in monocytes from apolipoprotein E-deficient (apoE−/−) mice compared with age-matched wild-type C57BL/6 (WT) mice. Experiments were performed in young (2-months) and in old (18-months) male wild-type (WT) and apoE−/− mice.ResultsBesides the expected differences in serum lipid profile and plaque formation, we observed that atherosclerotic mice exhibited a significant increase in monocytosis and in serum levels of pro-inflammatory cytokines compared to WT mice. Moreover, it was observed that the overproduction of ROS, led to an increased DNA fragmentation and, consequently, apoptosis in monocytes from normocholesterolemic old mice, which was aggravated in age-matched atherosclerotic mice.ConclusionsIn this study, we demonstrate that a pro-inflammatory systemic status is associated with an impairment of functionality of monocytes during aging and that these parameters are fundamental extra-arterial contributors to the aggravation of atherosclerosis. The present data open new avenues for the development of future strategies with the purpose of treating atherosclerosis.

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“…To understand the mechanisms underlying atherosclerosis development and progression and how it impacts cell function, we use apolipoprotein E deficient (apoE −/− ) mice [1][2][3]11], which show high levels of plasma cholesterol and develop atherosclerotic lesions that resemble human disease. Emerging evidence suggests the beneficial effects of phosphodiesterase 5 (PDE5) inhibition with sildenafil on cardiovascular diseases and other target organs [6,7,10,[12][13][14]. However, the effects of sildenafil on oxidative DNA damage in bone marrow cells from apoE −/− mice have yet to be characterized.…”

Section: Introductionmentioning

confidence: 99%

Protective effect of sildenafil on the genotoxicity and cytotoxicity in apolipoprotein E-deficient mice bone marrow cells

et al. 2016

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BackgroundThe pharmacological inhibitor of phosphodiesterase 5 (PDE5), sildenafil, is a promising candidate for antioxidant therapy that can result in cardiovascular protection. In addition to its known effects on the cardiovascular system, hypercholesterolemia leads to increased oxidative stress and DNA damage in the bone marrow, which is a non-classical target organ of atherosclerosis. In the present study, we evaluate oxidative stress and assess the effect of genomic instability on cell cycle kinetics in atherosclerotic animals and determine if sildenafil reverses these detrimental effects in bone marrow cells.MethodsExperiments were performed in male wild-type (WT) and apolipoprotein E knockout mice (apoE−/−) (9 weeks of age). apoE−/− mice were randomly distributed into the following 2 groups: sildenafil-treated (40 mg/kg/day for 3 weeks, n = 8) and vehicle-treated (n = 8), by oral gavage. After treatment, bone marrow cells were isolated to assess the production of superoxide anions and hydrogen peroxide, determine cell cycle kinetics and evaluate the presence of micronucleated cells.ResultsSildenafil treatment reduced the cytoplasmic levels of superoxide anion (~95 % decrease, p < 0.05) and decreased hydrogen peroxide (~30 % decrease, p < 0.05). Moreover, we observed protective effects on the DNA of bone marrow cells, including normal cell cycling, decreased DNA fragmentation and a diminished frequency of micronucleated cells.ConclusionOur data reveal that the excessive production of ROS in atherosclerotic mice overcome the DNA repair pathways in bone marrow cells. The novelty of the present study is that the administration of sildenafil reduced ROS to baseline levels and, consequently, reverted the DNA damage and its outcomes in bone marrow cells.

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Sildenafil ameliorates oxidative stress and DNA damage in the stenotic kidneys in mice with renovascular hypertension

Cited by 44 publications

References 77 publications

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

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

Increased ROS production and DNA damage in monocytes are biomarkers of aging and atherosclerosis

Protective effect of sildenafil on the genotoxicity and cytotoxicity in apolipoprotein E-deficient mice bone marrow cells

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