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

Campagnaro, Bianca Prandi; Tonini, Clarissa Loureiro; Doche, Luciano M.; Nogueira, Breno Valentim; Vasquez, Elisardo C.; Meyrelles, Silvana S.

doi:10.1089/dna.2013.2065

Cited by 17 publications

(29 citation statements)

References 72 publications

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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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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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“…This finding may be because high BP (enhanced shear stress) and activation of the RAS have been shown to increase ROS production by NAD(P)H oxidase via the AT 1 receptor axis, decreasing NO bioavailability in the 2K1C mice [27,30,45,65]. The hypothesis that it occurs an imbalance between NO and O 2 levels in the endothelial cells isolated from MAB, but not only systemically [21,30,31], was confirmed in a separated set of experiments by flow cytometry in the present study. Additionally, by using the HPF staining, we found in renovascular hypertensive mice an increase of endothelial production of peroxynitrite, which is derived from the reaction of NO with the superoxide anion.…”

Section: Discussionmentioning

confidence: 99%

Inhibition of phosphodiesterase 5 restores endothelial function in renovascular hypertension

et al. 2014

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BackgroundThe clipping of an artery supplying one of the two kidneys (2K1C) activates the renin-angiotensin (Ang) system (RAS), resulting in hypertension and endothelial dysfunction. Recently, we demonstrated the intrarenal beneficial effects of sildenafil on the high levels of Ang II and reactive oxygen species (ROS) and on high blood pressure (BP) in 2K1C mice. Thus, in the present study, we tested the hypothesis that sildenafil improves endothelial function in hypertensive 2K1C mice by improving the NO/ROS balance.Methods2K1C hypertension was induced in C57BL/6 mice. Two weeks later, they were treated with sildenafil (40 mg/kg/day, via oral) or vehicle for 2 weeks and compared with sham mice. At the end of the treatment, the levels of plasma and intrarenal Ang peptides were measured. Endothelial function and ROS production were assessed in mesenteric arterial bed (MAB).ResultsThe 2K1C mice exhibited normal plasma levels of Ang I, II and 1–7, whereas the intrarenal Ang I and II were increased (~35% and ~140%) compared with the Sham mice. Sildenafil normalized the intrarenal Ang I and II and increased the plasma (~45%) and intrarenal (+15%) Ang 1–7. The 2K1C mice exhibited endothelial dysfunction, primarily due to increased ROS and decreased NO productions by endothelial cells, which were ameliorated by treatment with sildenafil.ConclusionThese data suggest that the effects of sildenafil on endothelial dysfunction in 2K1C mice may be due to interaction with RAS and restoring NO/ROS balance in the endothelial cells from MAB. Thus, sildenafil is a promising candidate drug for the treatment of hypertension accompanied by endothelial dysfunction and kidney disease.

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“…The cell suspension was subsequently centrifuged for 10 min at 1200 rpm. The cells were counted and assessed for viability in Neubauer chamber [15]. The samples were considered viable when ≥ 90 % were found to be alive.…”

Section: Isolation Of Bone Marrow Cellsmentioning

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

Cited by 17 publications

References 72 publications

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

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

Inhibition of phosphodiesterase 5 restores endothelial function in renovascular hypertension

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

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