Maternal Treatment of Spontaneously Hypertensive Rats With Pentaerythritol Tetranitrate Reduces Blood Pressure in Female Offspring

Wu, Zijian; Siuda, Daniel; Xia, Ning; Reifenberg, Gisela; Daiber, Andreas; Münzel, Thomas; Förstermann, Ulrich; Li, Huige

doi:10.1161/hypertensionaha.114.04416

Cited by 43 publications

(52 citation statements)

References 25 publications

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“…36 Interestingly, evidence that therapeutic targeting of impaired NO signaling by soluble guanylyl cyclase activation or angiotensin-converting enzyme inhibition restores mitochondrial expression of UCP3 and SOD2 in the failing heart after MI 6 implies a critical role for NO in the regulation of the mitochondrial ROS detoxification system in chronic heart disease. In an elegant study, Wu et al 37 recently showed that maternal treatment of spontaneously hypertensive rats with PETN reduces blood pressure in female offspring, linked to epigenetic changes and transcriptional activation, in turn inducing antioxidant enzymes. Beneficial modulation of cardioprotective/cardiotoxic genes by PETN treatment has also been reported in the myocardium of healthy rats.…”

Section: Discussionmentioning

confidence: 99%

Pentaerythritol Tetranitrate Targeting Myocardial Reactive Oxygen Species Production Improves Left Ventricular Remodeling and Function in Rats With Ischemic Heart Failure

et al. 2015

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Reduced nitric oxide bioavailability contributes to progression of cardiac dysfunction and remodeling in ischemic heart failure. Clinical use of organic nitrates as nitric oxide donors is limited by development of nitrate tolerance and reactive oxygen species formation. We investigated the effects of long-term therapy with pentaerythritol tetranitrate (PETN), an organic nitrate devoid of tolerance, in rats with congestive heart failure after extensive myocardial infarction. Seven days after coronary artery ligation, rats were randomly allocated to treatment with PETN (80 mg/kg BID) or placebo for 9 weeks. Long-term PETN therapy prevented the progressive left ventricular dilatation and improved left ventricular contractile function and relaxation in rats with congestive heart failure. Mitochondrial superoxide anion production was markedly increased in the failing left ventricular myocardium and nearly normalized by PETN treatment. Gene set enrichment analysis revealed that PETN beneficially modulated the dysregulation of mitochondrial genes involved in energy metabolism, paralleled by prevention of uncoupling protein-3, thioredoxin-2, and superoxide dismutase-2 downregulation. Moreover, PETN provided a remarkable protective effect against reactive fibrosis in chronically failing hearts. Mechanistically, induction of heme oxygenase-1 by PETN prevented mitochondrial superoxide generation, NOX4 upregulation, and ensuing formation of extracellular matrix proteins in fibroblasts from failing hearts. In summary, PETN targeting reactive oxygen species generation prevented the changes of mitochondrial antioxidant enzymes and progressive fibrotic remodeling, leading to amelioration of cardiac functional performance. Therefore, PETN might be a promising therapeutic option in the treatment of ischemic heart diseases involving oxidative stress and impairment in nitric oxide bioactivity.

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Section: Discussionmentioning

confidence: 99%

Pentaerythritol Tetranitrate Targeting Myocardial Reactive Oxygen Species Production Improves Left Ventricular Remodeling and Function in Rats With Ischemic Heart Failure

et al. 2015

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“…Pentaerythritol tetranitrate (PETN), an organic nitrate devoid of adverse effects such as the induction of nitrate tolerance, vascular oxidative stress, and endothelial dysfunction, improves vascular function in diabetes mellitus and angiotensin II-induced vascular dysfunction. 5 In the present issue of Hypertension, Wu et al 6 report that treatment with PETN during pregnancy and lactation period in spontaneously hypertensive rats (SHR) reduced blood pressure in female offspring (Figure). Besides reduction of blood pressure at 6 and 8 months through maternal PETN treatment, endothelial-dependent relaxation was improved accompanied by increased NO bioavailability.…”

Section: See Related Article Pp 232-237mentioning

confidence: 93%

“…Epigenetic alterations in other organs involved in blood pressure regulation like the heart or kidney have been described and could also be involved in blood pressure reduction in female offspring induced by maternal PETN treatment. Indeed, changes in mRNA expression of the hypertension regulating genes elastin 1, epoxide hydrolase 2, and acylCoA synthetase medium-chain-family member 3 were found in the kidney of female offspring by Wu et al 6 How PETN did induce histone 3 lysine 27 acetylation and histone 3 lysine 4 trimethylation is not completely clear. Evidence exists that reactive oxygen species, in part, regulate histone modifications.…”

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confidence: 99%

NO for the Pregnant Mother

Bauersachs

Widder

2015

Hypertension

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T he cause of essential hypertension is multifactorial involving genetic aspects and accumulation of risk factors in adult life, including sedentary lifestyle, adiposity, smoking, and stress. Accumulating evidence exists, however, that the development of future hypertension in the offspring can be directly related to adverse conditions during pregnancy and early life span, like intrauterine malnutrition, stress-induced constriction of placental vessels, exposure of the fetus to nicotine, alcohol, pesticides, drugs, and environmental toxins.1 Pregnant women display a 5% to 7% risk of developing new onset high blood pressure with a variety of hypertensive complications ranging from gestational hypertension to severe preeclampsia leading to organ damage. Furthermore, offspring of these mothers have a markedly increased risk for development of hypertension.This delayed evolution of hypertension seems to be linked to the phenomenon of epigenetic changes occurring during pregnancy and early life span which was confirmed by numerous studies in animals and humans. Epigenetic modifications lead to alterations in gene expression or phenotype without any changes in the underlying DNA sequence. They include DNA methylation, post-translational histone modifications, and noncoding RNAs.2 In preeclampsia, for example, epigenetic changes are found in the placenta with differences in the expression profiles of endogenous serine protease inhibitors. Reduced nitric oxide (NO) levels leading to endothelial dysfunction have been implicated in the onset and progression of essential hypertension as well as in pregnancyassociated hypertension. nitric oxide (NO) is oxidized by superoxide anions to peroxynitrite and subsequently nitrite and nitrate. NO-mediated vasodilatation thereby is diminished and vasoconstriction augmented with a subsequent increase in systemic vascular resistance. 4 Increasing NO availability therefore is an interesting treatment target. Organic nitrates liberating NO or a related molecule are part of the standard drug treatment for patients with angina pectoris secondary to coronary artery disease. NO liberation stimulates soluble guanylate cyclase in smooth muscle cells to enhance formation of cyclic guanosine monophosphate leading to relaxation, thus replacing the diminished endogenous vasodilator capacity. However, the potential of most organic nitrates is limited by the development of tolerance and induction of reactive oxygen formation and endothelial dysfunction. Pentaerythritol tetranitrate (PETN), an organic nitrate devoid of adverse effects such as the induction of nitrate tolerance, vascular oxidative stress, and endothelial dysfunction, improves vascular function in diabetes mellitus and angiotensin II-induced vascular dysfunction. 5In the present issue of Hypertension, Wu et al 6 report that treatment with PETN during pregnancy and lactation period in spontaneously hypertensive rats (SHR) reduced blood pressure in female offspring (Figure). Besides reduction of blood pressure at 6 and 8 months through ...

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“…After removal of the beads, the eluate was purified with the QIAQuick PCR Purification Kit (Qiagen #28104). Immunoprecipitated DNA was subjected to qPCR analysis using promoter-specific primers for eNOS [38], NOS2, RAGE and IFNγ (predicted from the UCSC genome browser: https://genome.ucsc.edu/). Chip data were calculated relative to input.…”

Section: Chromatin Immunoprecipitation (Chip)mentioning

confidence: 99%

The SGLT2 Inhibitor Empagliflozin Improves the Primary Diabetic Complications in ZDF Rats

Hanf

Steven

Oelze

et al. 2017

Free Radical Biology and Medicine

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A B S T R A C THyperglycemia associated with inflammation and oxidative stress is a major cause of vascular dysfunction and cardiovascular disease in diabetes. Recent data reports that a selective sodium-glucose co-transporter 2 inhibitor (SGLT2i), empagliflozin (Jardiance ® ), ameliorates glucotoxicity via excretion of excess glucose in urine (glucosuria) and significantly improves cardiovascular mortality in type 2 diabetes mellitus (T2DM). The overarching hypothesis is that hyperglycemia and glucotoxicity are upstream of all other complications seen in diabetes. The aim of this study was to investigate effects of empagliflozin on glucotoxicity, β-cell function, inflammation, oxidative stress and endothelial dysfunction in Zucker diabetic fatty (ZDF) rats. Male ZDF rats were used as a model of T2DM (35 diabetic ZDF-Lepr fa/fa and 16 ZDF-Lepr +/+ controls). Empagliflozin (10 and 30 mg/kg/d) was administered via drinking water for 6 weeks. Treatment with empagliflozin restored glycemic control. Empagliflozin improved endothelial function (thoracic aorta) and reduced oxidative stress in the aorta and in blood of diabetic rats. Inflammation and glucotoxicity (AGE/RAGE signaling) were epigenetically prevented by SGLT2i treatment (ChIP). Linear regression analysis revealed a significant inverse correlation of endothelial function with HbA1c, whereas leukocyte-dependent oxidative burst and C-reactive protein (CRP) were positively correlated with HbA1c. Viability of hyperglycemic endothelial cells was pleiotropically improved by SGLT2i. Empagliflozin reduces glucotoxicity and thereby prevents the development of endothelial dysfunction, reduces oxidative stress and exhibits anti-inflammatory effects in ZDF rats, despite persisting hyperlipidemia and hyperinsulinemia. Our preclinical observations provide insights into the mechanisms by which empagliflozin reduces cardiovascular mortality in humans (EMPA-REG trial).

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Maternal Treatment of Spontaneously Hypertensive Rats With Pentaerythritol Tetranitrate Reduces Blood Pressure in Female Offspring

Cited by 43 publications

References 25 publications

Pentaerythritol Tetranitrate Targeting Myocardial Reactive Oxygen Species Production Improves Left Ventricular Remodeling and Function in Rats With Ischemic Heart Failure

Pentaerythritol Tetranitrate Targeting Myocardial Reactive Oxygen Species Production Improves Left Ventricular Remodeling and Function in Rats With Ischemic Heart Failure

NO for the Pregnant Mother

The SGLT2 Inhibitor Empagliflozin Improves the Primary Diabetic Complications in ZDF Rats

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