Heme oxygenase-1 deficiency exacerbates angiotensin II-induced aortic aneurysm in mice

Chen

et al. 2018

British J Pharmacology

Background and Purpose Abdominal aortic aneurysm (AAA) is a degenerative disease affecting human health, but there are no safe and effective medications for AAA therapy. Cycloastragenol (CAG), derived from Astragali Radix, has various pharmacological effects. However, whether CAG can protect against AAA remains elusive. In this study, we investigated whether CAG has an inhibitory effect on AAA and its related mechanism. Experimental Approach The AAA mouse model was induced by incubating the abdominal aorta with elastase. CAG was administered by gavage at different doses beginning on the same day or 14 days after inducing AAA to explore its preventive or therapeutic effects respectively. The preventive effects of CAG on AAA were verified in another AAA mouse model induced by angiotensin II in ApoE−/− mouse. In vitro experiments were implemented on rat vascular smooth muscle cells (VSMCs) stimulated by TNF‐α. Key Results Compared to the control AAA model group, CAG (125 mg·kg−1 body weight day−1) reduced the incidence of AAA, the dilatation of aorta and elastin degradation in media in both mouse models of AAA. CAG suppressed the inflammation, oxidation, phenotype switch and apoptosis in TNF‐α‐stimulated VSMCs, ameliorated the expression and activity of MMPs and decreased the activation of the ERK/JNK signalling pathway. CAG also inhibited the degradation of elastin in TNF‐α‐stimulated VSMCs. Conclusion and Implications CAG presents protective effects against AAA through down‐regulation of the MAPK signalling pathways and thus attenuates inflammation, oxidation, VSMC phenotype switch and apoptosis and the expression of MMPs as well as increasing elastin biosynthesis.

Section: Discussionmentioning

confidence: 99%

Inhibitory effects of cycloastragenol on abdominal aortic aneurysm and its related mechanisms

Chen

et al. 2018

British J Pharmacology

Oxidative Medicine and Cellular Longevity

“…To detect renal ROS production, an in situ dihydroethidium (DHE, Sigma-Aldrich, USA) fluorescence was performed [ 19 ]. Kidney frozen sections (5 μ m) were incubated with 1 μ mol/l DHE at 37°C in a light-protected, humidified chamber at room temperature for 30 min.…”

Section: Methodsmentioning

confidence: 99%

RTA‐408 Protects Kidney from Ischemia‐Reperfusion Injury in Mice via Activating Nrf2 and Downstream GSH Biosynthesis Gene

Han

Qin

Tang

et al. 2017

Acute kidney injury (AKI) induced by ischemia-reperfusion is a critical conundrum in many clinical settings. Here, this study aimed to determine whether and how RTA-408, a novel oleanane triterpenoid, could confer protection against renal ischemia-reperfusion injury (IRI) in male mice. Mice treated with RTA-408 undergoing unilateral ischemia followed by contralateral nephrectomy had improved renal function and histological outcome, as well as decreased apoptosis, ROS production, and oxidative injury marker compared with vehicle-treated mice. Also, we had found that RTA-408 could strengthen the total antioxidant capacity by increasing Nrf2 nuclear translocation and subsequently increased Nrf2 downstream GSH-related antioxidant gene expression and activity. In vitro study demonstrated that GSH biosynthesis enzyme GCLc could be an important target of RTA-408. Furthermore, Nrf2-deficient mice treated with RTA-408 had no significant improvement in renal function, histology, ROS production, and GSH-related gene expression. Thus, by upregulating Nrf2 and its downstream antioxidant genes, RTA-408 presents a novel and potential approach to renal IRI prevention and therapy.

“…In addition, catalase overexpression in aortic smooth muscle cells prevented pathological mechanical changes underlying AAA formation [ 168 , 169 ]. In addition, hemoxygenase-1 deficiency aggravates Angiotesin-II induced aortic aneurysms in the ApoE −/− model [ 170 ].…”

Section: Antioxidants As a Potential Therapeutic Strategy To Prevementioning

confidence: 99%

Oxidative Stress in Human Atherothrombosis: Sources, Markers and Therapeutic Targets

Martin-Ventura

Rodrigues‐Díez

Martínez-López

et al. 2017

IJMS

Atherothrombosis remains one of the main causes of morbidity and mortality worldwide. The underlying pathology is a chronic pathological vascular remodeling of the arterial wall involving several pathways, including oxidative stress. Cellular and animal studies have provided compelling evidence of the direct role of oxidative stress in atherothrombosis, but such a relationship is not clearly established in humans and, to date, clinical trials on the possible beneficial effects of antioxidant therapy have provided equivocal results. Nicotinamide adenine dinucleotide phosphate (NADPH) oxidase is one of the main sources of reactive oxygen species (ROS) in human atherothrombosis. Moreover, leukocyte-derived myeloperoxidase (MPO) and red blood cell-derived iron could be involved in the oxidative modification of lipids/lipoproteins (LDL/HDL) in the arterial wall. Interestingly, oxidized lipoproteins, and antioxidants, have been analyzed as potential markers of oxidative stress in the plasma of patients with atherothrombosis. In this review, we will revise sources of ROS, focusing on NADPH oxidase, but also on MPO and iron. We will also discuss the impact of these oxidative systems on LDL and HDL, as well as the value of these modified lipoproteins as circulating markers of oxidative stress in atherothrombosis. We will finish by reviewing some antioxidant systems and compounds as therapeutic strategies to prevent pathological vascular remodeling.