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Pentaerythritol Tetranitrate In Vivo Treatment Improves Oxidative Stress and Vascular Dysfunction by Suppression of Endothelin-1 Signaling in Monocrotaline-Induced Pulmonary Hypertension.

ABSTRACT: Objective. Oxidative stress and endothelial dysfunction contribute to pulmonary arterial hypertension (PAH). The role of the nitrovasodilator pentaerythritol tetranitrate (PETN) on endothelial function and oxidative stress in PAH has not yet been defined. Methods and Results. PAH was induced by monocrotaline (MCT, i.v.) in Wistar rats. Low (30?mg/kg; MCT30), middle (40?mg/kg; MCT40), or high (60?mg/kg; MCT60) dose of MCT for 14, 28, and 42?d was used. MCT induced endothelial dysfunction, pulmonary vascular wall thickening, and fibrosis, as well as protein tyrosine nitration. Pulmonary arterial pressure and heart/body and lung/body weight ratio were increased in MCT40 rats (28?d) and reduced by oral PETN (10?mg/kg, 24?d) therapy. Oxidative stress in the vascular wall, in the heart, and in whole blood as well as vascular endothelin-1 signaling was increased in MCT40-treated rats and normalized by PETN therapy, likely by upregulation of heme oxygenase-1 (HO-1). PETN therapy improved endothelium-dependent relaxation in pulmonary arteries and inhibited endothelin-1-induced oxidative burst in whole blood and the expression of adhesion molecule (ICAM-1) in endothelial cells. Conclusion. MCT-induced PAH impairs endothelial function (aorta and pulmonary arteries) and increases oxidative stress whereas PETN markedly attenuates these adverse effects. Thus, PETN therapy improves pulmonary hypertension beyond its known cardiac preload reducing ability.

SUBMITTER: Steven S

PROVIDER: S-EPMC5350298 | biostudies-literature | 2017

REPOSITORIES: biostudies-literature

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Pentaerythritol Tetranitrate In Vivo Treatment Improves Oxidative Stress and Vascular Dysfunction by Suppression of Endothelin-1 Signaling in Monocrotaline-Induced Pulmonary Hypertension.

Steven Sebastian S Oelze Matthias M Brandt Moritz M Ullmann Elisabeth E Kröller-Schön Swenja S Heeren Tjebo T Tran Lan P LP Daub Steffen S Dib Mobin M Stalleicken Dirk D Wenzel Philip P Münzel Thomas T Daiber Andreas A

Oxidative medicine and cellular longevity 20170228

<i>Objective</i>. Oxidative stress and endothelial dysfunction contribute to pulmonary arterial hypertension (PAH). The role of the nitrovasodilator pentaerythritol tetranitrate (PETN) on endothelial function and oxidative stress in PAH has not yet been defined. <i>Methods and Results</i>. PAH was induced by monocrotaline (MCT, i.v.) in Wistar rats. Low (30 mg/kg; MCT30), middle (40 mg/kg; MCT40), or high (60 mg/kg; MCT60) dose of MCT for 14, 28, and 42 d was used. MCT induced endothelial dysfun ...[more]

PMID: 28337251

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Project description:In this paper, ReaxFF force field combined with molecular dynamics method was used to study the ignition, deflagration, and detonation of pentaerythritol tetranitrate (PETN) induced by hot spots. The hot spot is 5.6% of the total volume. When the hot spot temperature is 1000 K, the deflagration and detonation of PETN cannot be observed in the simulation time of 200 ps. When the hot spot temperature is 2000 K, it corresponds to the heating time of 20 to 50 ps, deflation and detonation were observed. During hot spot ignition, the products of decomposition of the condensed phase PETN are dominated by NO2 and HONO. The energy required for the C-C bond and C-ONO2 bond cleavage in PETN is high, resulting in only a small amount of CH2O and NO3 during the reaction. Small nitrogen-containing molecules (such as NO2, NO3, HONO, HNO3, etc.) mainly exist during thermal equilibrium, while the number of N2 increases sharply during the thermal runaway stage, and a small amount of NH3 and NH2 are also produced. H2O molecules are formed before CO2 and N2 are produced, and the number always dominates. During the thermal runaway, the entire system can maintain a spontaneous reaction, resulting in a sharp rise in temperature of about 2500 K in 20 ps. During this phase, the catalytic effect of H2O accelerates the formation of CO2 and N2 due to the near Chapman-Jouguet point in the crystal. PETN is a weak oxygen balance explosive that results in a small amount of CO and H2 production during the thermal instability phase. When the reaction is balanced, the relative molecular mass is close to or exceeds that of PETN. The product is only less than 1% of the total mass fraction, while the small molecule product is as high as 78%, and some relative molecular masses are [75,225]. The intermediates account for about 21%. Rapid and complex reaction events make it difficult to accurately predict the structure of these intermediates by existing experiments and calculations, which will be the focus of future research.

Project description:Aims:Current antihypertensive therapies cannot cure hypertension and a life-long medication is necessary. Maternal treatment may represent a promising strategy for hypertension treatment. We have previously shown that maternal treatment of spontaneously hypertensive rats (SHR) with pentaerythritol tetranitrate (PETN) leads to a persistent blood pressure reduction in the female offspring. The underlying mechanisms include improved endothelial function resulting from long-lasting epigenetic changes. In the present study, we address the renal effects of maternal PETN treatment. Methods and Results:F0 parental SHR were fed with either normal chow or PETN-containing (1 g/kg) chow ad libitum from the time point of mating to the end of lactation period. The F1 offspring received normal chow without PETN from the time point of weaning (at the age of 3 weeks). At the age of 16 weeks, female PETN offspring showed lower blood pressure than the control. No difference was observed in male offspring. All following experiments were performed with kidneys from 16-week-old female offspring. Maternal PETN treatment reduced the mRNA and protein expression of angiotensin-converting enzyme (ACE) and basic fibroblast growth factor (FGF2), resulting from epigenetic modifications found at the proximal promoter regions. The expression levels of mineralocorticoid receptor (MR) and factors in the MR signalling pathway (Rac1 and Sgk1) were also reduced by PETN. Major profibrotic cytokines, including Wnt4, TNF-alpha, TGF-beta, and MMP9, were downregulated by PETN, which was associated with reduced collagen deposition and glomerulus sclerosis in the kidney of PETN offspring. In addition, PETN treatment also decreased the markers of inflammation and immune cell infiltration in the kidneys. Conclusions:PETN maternal treatment leads to epigenetic changes in the kidney of female SHR offspring. The reduced renal inflammation, alleviated kidney fibrosis, and decreased MR signalling are potential mechanisms contributing to the observed blood pressure-lowering effect.

Project description:Preeclampsia is a common medical condition during pregnancy and a major cause of maternal and prenatal mortality. The present study was conducted to investigate the effects of maternal treatment with pentaerythritol tetranitrate (PETN) in Dahl salt-sensitive rats (DSSR), a model of superimposed preeclampsia. F0 parental DSSR were treated with PETN (50 mg/kg) from the time point of mating to the end of lactation. Maternal PETN treatment improved fetal growth and had no effect on blood pressure in DSSR offspring fed with normal chow or high-salt diet. Upon high-fat diet (HFD) feeding, offspring from PETN-treated mother showed improved glucose tolerance despite similar weight gain. Unexpectedly, maternal PETN treatment significantly potentiated the HFD-induced blood pressure elevation in male DSSR offspring. Endothelium-derived hyperpolarization factor (EDHF)-mediated vasodilation was similar between NCD-fed and HFD-fed control offspring but was markedly reduced in HFD-fed PETN offspring. EDHF genes were downregulated in the vasculature of HFD-fed PETN offspring, which was associated with epigenetic changes in histone modifications. In conclusion, maternal PETN treatment in DSSR shows both beneficial and unfavorable effects. It improves fetal growth and ameliorates glucose tolerance in the offspring. Although maternal PETN treatment has no effect on blood pressure in offspring fed with normal chow or high-salt diet, the offspring is at higher risk to develop HFD-induced hypertension. PETN may potentiate the blood pressure response to HFD by epigenetic modifications of EDHF genes. KEY MESSAGES: The core findings of this article suggest that maternal PETN treatment of DSSR, a rat model of a spontaneous superimposed preeclampsia, leads to • Improvement of fetal growth; • No changes of maternal blood pressure or markers of preeclampsia; • Amelioration of HFD-induced glucose intolerance in adult offspring; • No changes in blood pressure development of the offspring on normal chow or high salt-diet; • Potentiation of blood pressure elevation of the offspring on HFD.

Project description:RationaleHypertension represents a major risk factor for stroke, myocardial infarction, and heart failure and affects 30% of the adult population. Mitochondrial dysfunction contributes to hypertension, but specific mechanisms are unclear. The mitochondrial deacetylase Sirt3 (Sirtuin 3) is critical in the regulation of metabolic and antioxidant functions which are associated with hypertension, and cardiovascular disease risk factors diminish Sirt3 level.ObjectiveWe hypothesized that reduced Sirt3 expression contributes to vascular dysfunction in hypertension, but increased Sirt3 protects vascular function and decreases hypertension.Methods and resultsTo test the therapeutic potential of targeting Sirt3 expression, we developed new transgenic mice with global Sirt3OX (Sirt3 overexpression), which protects from endothelial dysfunction, vascular oxidative stress, and hypertrophy and attenuates Ang II (angiotensin II) and deoxycorticosterone acetate-salt induced hypertension. Global Sirt3 depletion in Sirt3-/- mice results in oxidative stress due to hyperacetylation of mitochondrial superoxide dismutase (SOD2), increases HIF1α (hypoxia-inducible factor-1), reduces endothelial cadherin, stimulates vascular hypertrophy, increases vascular permeability and vascular inflammation (p65, caspase 1, VCAM [vascular cell adhesion molecule-1], ICAM [intercellular adhesion molecule-1], and MCP1 [monocyte chemoattractant protein 1]), increases inflammatory cell infiltration in the kidney, reduces telomerase expression, and accelerates vascular senescence and age-dependent hypertension; conversely, increased Sirt3 expression in Sirt3OX mice prevents these deleterious effects. The clinical relevance of Sirt3 depletion was confirmed in arterioles from human mediastinal fat in patients with essential hypertension showing a 40% decrease in vascular Sirt3, coupled with Sirt3-dependent 3-fold increases in SOD2 acetylation, NF-κB (nuclear factor kappa-light-chain-enhancer of activated B cells) activity, VCAM, ICAM, and MCP1 levels in hypertensive subjects compared with normotensive subjects.ConclusionsWe suggest that Sirt3 depletion in hypertension promotes endothelial dysfunction, vascular hypertrophy, vascular inflammation, and end-organ damage. Our data support a therapeutic potential of targeting Sirt3 expression in vascular dysfunction and hypertension.

Dataset Information

Pentaerythritol Tetranitrate In Vivo Treatment Improves Oxidative Stress and Vascular Dysfunction by Suppression of Endothelin-1 Signaling in Monocrotaline-Induced Pulmonary Hypertension.

Publications

Pentaerythritol Tetranitrate In Vivo Treatment Improves Oxidative Stress and Vascular Dysfunction by Suppression of Endothelin-1 Signaling in Monocrotaline-Induced Pulmonary Hypertension.

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