Sildenafil reduces signs of oxidative stress in pulmonary arterial hypertension: Evaluation by fatty acid composition, level of hydroxynonenal and heart rate variability

Semen, Khrystyna; Yelisyeyeva, Olha; Jarocka-Karpowicz, Iwona; Kaminskyy, Danylo; Solovey, Lyubomyr; Skrzydlewska, Elżbieta; Yavorskyi, Ostap

doi:10.1016/j.redox.2015.11.009

Cited by 35 publications

(27 citation statements)

References 79 publications

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“…This finding corresponds with previous investigations that showed the ability of vardenafil to suppress nitro-oxidative damage in the aortic endothelium and rat ovary [24,25]. Additionally, other PDE-5 inhibitors have been reported to have potential antioxidative effects in other models of oxidative injury [26][27][28][29].…”

Section: Discussionsupporting

confidence: 92%

Anti-Inflammatory Effects of Vardenafil Against Cholestatic Liver Damage in Mice: a Mechanistic Study

El‐Agamy

Almaramhy

Ahmed

et al. 2018

Cell Physiol Biochem

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Background/Aims: Phosphodiesterase-5 inhibitors have beneficial effects in multiple liver diseases possibly through the reduction of oxidative stress and inflammatory response. However, these effects have not yet been examined in cholestatic liver dysfunction. Hence, this study aimed to explore the ability of vardenafil, a known phosphodiesterase-5 inhibitor, to repress lithocholic acid (LCA)-induced cholestatic liver injury and investigate the possible molecular pathways. Methods: Male Swiss albino mice were treated with LCA (0.125 mg/g) twice daily for 7 days to induce cholestatic liver damage. Vardenafil was administered 3 days before and throughout the administration of LCA. Serum markers of hepatotoxicity and hepatic nitro-oxidative stress along with antioxidant parameters were measured, and the histopathology of liver tissues was assessed. The expression of nuclear factor erythroid 2-related factor 2 (Nrf2) and its target genes was examined using PCR. The activation of nuclear factor kappa-B (NF-κB) and the levels of inflammatory cytokines were determined. NLRP3 inflammasome and its components were studied by PCR and western blot. Results: LCA induced marked cholestatic liver damage as demonstrated by increased serum transaminases, alkaline phosphatase (ALP), lactate dehydrogenase (LDH), bilirubin, and bile acids. Examination of liver specimens confirmed the biochemical results. Nitro-oxidative stress parameters were significantly elevated along with reduced antioxidant capacity in hepatic tissue following LCA administration. LCA suppressed Nrf2 and its target genes and decreased the mRNA expression and binding capacity of Nrf2 as well as the mRNA expression of GCLm, GCLc, Nqo1, and HO-1. Additionally, LCA enhanced the activation of NF-κB, which was accompanied by elevations of inflammatory cytokines. Importantly, LCA induced the activation of NLRP3 inflammasome. LCA increased the expression of NLRP3, ASC, caspase-1, and IL-1β genes and proteins in hepatic tissue. The activities of IL-1β and caspase-1 were increased in the LCA group. Interestingly, vardenafil ameliorated LCA-induced hepatic injury and alleviated all biochemical, histopathological, and inflammatory parameters. Conclusions: These data elucidated the effects of Nrf2 inhibition and NLRP3 inflammasome activation in LCA-induced liver injury. The hepatoprotective activity of vardenafil in LCA-induced cholestatic damage may result from the drug’s ability to activate Nrf2 signaling and prevent the activation of NLRP3, which could suppress the inflammatory responses in hepatic tissue. Thus, vardenafil can be considered a novel anti-inflammatory remedy for cholestatic liver damage.

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Section: Discussionsupporting

confidence: 92%

Anti-Inflammatory Effects of Vardenafil Against Cholestatic Liver Damage in Mice: a Mechanistic Study

El‐Agamy

Almaramhy

Ahmed

et al. 2018

Cell Physiol Biochem

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“…Usually, reduced HRV (low values of total power (TP), low percentage of low frequency (LF) and high frequency (HF) bands in the spectral structure) is accompanied by increased levels of the well‐recognized biochemical markers of OS and disorders in the pro‐/antioxidant balance. Such inverse relationships were demonstrated for lipidomic indices (levels of plasma triglycerides, cholesterol, low‐density lipoprotein and high‐density lipoprotein) and for MDA (Apaijai et al ., ; Supakul et al ., ) and HNE (Semen et al ., ). However, such correlations between HRV indices and certain OS biomarkers does not occur in a uniform pattern.…”

Section: Can Heart Rate Variability Reflect Severity Of Oxidative Strmentioning

confidence: 97%

“…The cardiorespiratory system is sensitive even to very small shifts in pO 2 , pCO 2 and also pH, which reflect the efficacy of aerobic metabolism and thus the degree of oxidative damage (Semen et al ., ; Yelisyeyeva et al ., ). It is widely accepted that diseases associated with OS such as diabetes, cardiovascular, neurodegenerative and inflammatory disorders, are characterized by reduced HRV (Lahiri et al ., ; LaRovere and Christensen, ; Semen et al ., ). Usually, reduced HRV (low values of total power (TP), low percentage of low frequency (LF) and high frequency (HF) bands in the spectral structure) is accompanied by increased levels of the well‐recognized biochemical markers of OS and disorders in the pro‐/antioxidant balance.…”

Section: Can Heart Rate Variability Reflect Severity Of Oxidative Strmentioning

confidence: 98%

Biomarkers of oxidative and nitro‐oxidative stress: conventional and novel approaches

Gašparović

Žarković

et al. 2017

British J Pharmacology

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The concept of oxidative stress (OS) that connects altered redox biology with various diseases was introduced 30 years ago and has generated intensive research over the past two decades. Whereas it is now commonly accepted that macromolecule oxidation in response to ROS is associated with a variety of pathologies, the emergence of NO as a key regulator of redox signalling has led to the discovery of the pathophysiological significance of reactive nitrogen species (RNS). RNS can elicit various modifications of macromolecules and lead to nitrative or nitro-OS. In order to investigate oxidative and nitro-OS in human and in live animal models, circulating biomarker assays have been developed. This article provides an overview of key biomarkers used to assess lipid peroxidation and NO/NO 2 signalling, thereby stressing the necessity to analyse several OS biomarkers in relation to the overall (aerobic) metabolism and health condition of patients. In addition, the potential interest of heart rate variability as the non-invasive integrative biomarker of OS is discussed. LINKED ARTICLESThis article is part of a themed section on Redox Biology and Oxidative Stress in Health and Disease. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v174.12/issuetoc Abbreviations 4-HNE, trans-4-hydroxy-2-nonenal; ACR, acrolein; ALE, advanced lipoxidation end-products; DNP, 2,4-dinitrophenylhydrazine; FRR, free radical reaction; HRV, heart rate variability; LO, lipid alkoxyl radical; LOO, lipid peroxyl radical; LOOH, lipid hydroperoxide; LPO, lipid peroxidation; MDA, malondialdehyde; NO + , nitrosonium ion; Nrf2, Nuclear factor (erythroid-derived 2)-like 2; OMP, oxidatively modified protein; OS, oxidative stress; PUFA, polyunsaturated fatty acids; RNS, reactive nitrogen species; TBARS, thiobarbituric acid reactive substances; UPR, unfolded protein response IntroductionOxidative stress (OS), which was first introduced as a concept in redox biology and medicine in 1985 by Helmut Sies and Enrique Cadenas (Cadenas and Sies, 1985;Sies and Cadenas, 1985), has gained increasing interest over the years to become a major field of investigation in chemistry, life sciences and medicine.This concept connects oxidative chemistry with biological stress responses. However, it has the disadvantage of concealing redox chemistry, which plays a key role in cell homeostasis and signalling and in physiology, which is, for a large part, dependent on both oxidation and reduction reactions (Frein et al., 2005). This complex field of biochemistry, which plays a key role in the regulation of a variety of enzymes involved in essential signalling pathways, is now referred to as 'redox signalling' (Ullrich and Kissner, 2006) (Figure 1 et al., 2015). This reaction gives rise to peroxynitrite (ONOO À ), which is a highly reactive nitrogen species (RNS), producing nitration and nitrosation of substrates, often proteins that play important pathophysiological roles (Ullrich and Kissner, 2006;Schulz et al., 2008;Bottari, 20...

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“…4-HNE has been reported to stimulate the proliferation of vascular smooth muscle cells [10], [11], [12]. The accumulation of 4-HNE in the pulmonary arteries in patients with PAH has been recognized as an important contributor to disease progression [13], [14]; however, the role of 4-HNE in the abnormal proliferation of pulmonary vascular smooth muscle cells, and the associated signaling pathways involved remain unknown.…”

Section: Introductionmentioning

confidence: 99%

Aldehyde dehydrogenase 2 protects against oxidative stress associated with pulmonary arterial hypertension

Liu

et al. 2017

Redox Biology

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The cardioprotective benefits of aldehyde dehydrogenase 2 (ALDH2) are well established, although the regulatory role of ALDH2 in vascular remodeling in pulmonary arterial hypertension (PAH) is largely unknown. ALDH2 potently regulates the metabolism of aldehydes such as 4-hydroxynonenal (4-HNE), the endogenous product of lipid peroxidation. Thus, we hypothesized that ALDH2 ameliorates the proliferation and migration of human pulmonary artery smooth muscle cells (HPASMCs) by inhibiting 4-HNE accumulation and regulating downstream signaling pathways, thereby ameliorating pulmonary vascular remodeling. We found that low concentrations of 4-HNE (0.1 and 1 μM) stimulated cell proliferation by enhancing cyclin D1 and c-Myc expression in primary HPASMCs. Low 4-HNE concentrations also enhanced cell migration by activating the nuclear factor kappa B (NF-κB) signaling pathway, thereby regulating matrix metalloprotein (MMP)-9 and MMP2 expression in vitro. In vivo, Alda-1, an ALDH2 agonist, significantly stimulated ALDH2 activity, reducing elevated 4-HNE and malondialdehyde levels and right ventricular systolic pressure in a monocrotaline-induced PAH animal model to the level of control animals. Our findings indicate that 4-HNE plays an important role in the abnormal proliferation and migration of HPASMCs, and that ALDH2 activation can attenuate 4-HNE-induced PASMC proliferation and migration, possibly by regulating NF-κB activation, in turn ameliorating vascular remodeling in PAH. This mechanism might reflect a new molecular target for treating PAH.

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Sildenafil reduces signs of oxidative stress in pulmonary arterial hypertension: Evaluation by fatty acid composition, level of hydroxynonenal and heart rate variability

Cited by 35 publications

References 79 publications

Anti-Inflammatory Effects of Vardenafil Against Cholestatic Liver Damage in Mice: a Mechanistic Study

Anti-Inflammatory Effects of Vardenafil Against Cholestatic Liver Damage in Mice: a Mechanistic Study

Biomarkers of oxidative and nitro‐oxidative stress: conventional and novel approaches

Aldehyde dehydrogenase 2 protects against oxidative stress associated with pulmonary arterial hypertension

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