Sussan TE, Rangasamy T, Blake DJ, Malhotra D, El-Haddad H, Bedja D, et al. Targeting Nrf2 with the triterpenoid CDDO-imidazolide attenuates cigarette smoke-induced emphysema and cardiac dysfunction in mice

Department of Environmental Health Sciences, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, MD 21205, USA.
Proceedings of the National Academy of Sciences (Impact Factor: 9.67). 01/2009; 106(1):250-5. DOI: 10.1073/pnas.0804333106
Source: PubMed


Chronic obstructive pulmonary disease (COPD), which comprises emphysema and chronic bronchitis resulting from prolonged exposure to cigarette smoke (CS), is a major public health burden with no effective treatment. Emphysema is also associated with pulmonary hypertension, which can progress to right ventricular failure, an important cause of morbidity and mortality among patients with COPD. Nuclear erythroid 2 p45 related factor-2 (Nrf2) is a redox-sensitive transcription factor that up-regulates a battery of antioxidative genes and cytoprotective enzymes that constitute the defense against oxidative stress. Recently, it has been shown that patients with advanced COPD have a decline in expression of the Nrf2 pathway in lungs, suggesting that loss of this antioxidative protective response is a key factor in the pathophysiological progression of emphysema. Furthermore, genetic disruption of Nrf2 in mice causes early-onset and severe emphysema. The present study evaluated whether the strategy of activation of Nrf2 and its downstream network of cytoprotective genes with a small molecule would attenuate CS-induced oxidative stress and emphysema. Nrf2(+/+) and Nrf2(-/-) mice were fed a diet containing the potent Nrf2 activator, 1-[2-cyano-3-,12-dioxooleana-1,9(11)-dien-28-oyl]imidazole (CDDO-Im), while being exposed to CS for 6 months. CDDO-Im significantly reduced lung oxidative stress, alveolar cell apoptosis, alveolar destruction, and pulmonary hypertension in Nrf2(+/+) mice caused by chronic exposure to CS. This protection from CS-induced emphysema depended on Nrf2, as Nrf2(-/-) mice failed to show significant reduction in alveolar cell apoptosis and alveolar destruction after treatment with CDDO-Im. These results suggest that targeting the Nrf2 pathway during the etiopathogenesis of emphysema may represent an important approach for prophylaxis against COPD.

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Available from: Deepti Malhotra, Dec 24, 2013
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    • "Recently, it has been shown that chronic cigarette smoke exposure enlarged ventricular end systolic and diastolic diameters, reduced myocardial and cardiomyocyte contractile function and disrupted intracellular Ca 2 þ homeostasis, and facilitated fibrosis, apoptosis and mitochondrial damage (Hu et al., 2013). Sussan et al. (2009) also showed that mice chronically exposed to cigarette smoke that had chronic lung inflammation and emphysema had pulmonary hypertensinon and significant impairments to right ventricle diastolic and systolic function and contractility. In addition, Beckett et al. (2013) found that hearts from mice exposed to cigarette smoke for 8 weeks that had pulmonary impairments were significantly larger and heavier than air-exposed mice. "
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    ABSTRACT: Chronic Obstructive Pulmonary Disease (COPD) is a major incurable global health burden and is the 4(th) leading cause of death worldwide. It is believed that an exaggerated inflammatory response to cigarette smoke causes progressive airflow limitation. This inflammation, where macrophages, neutrophils and T lymphocytes are prominent, leads to oxidative stress, emphysema, small airway fibrosis and mucus hypersecretion. Much of the disease burden and health care utilisation in COPD is associated with the management of its comorbidities and infectious (viral and bacterial) exacerbations (AECOPD). Comorbidities, defined as other chronic medical conditions, in particular skeletal muscle wasting and cardiovascular disease markedly impact on disease morbidity, progression and mortality. The mechanisms and mediators underlying COPD and its comorbidities are poorly understood and current COPD therapy is relatively ineffective. Thus, there is an obvious need for new therapies that can prevent the induction and progression of COPD and effectively treat AECOPD and comorbidities of COPD. Given that access to COPD patients can be difficult and that clinical samples often represent a "snapshot" at a particular time in the disease process, many researchers have used animal modelling systems to explore the mechanisms underlying COPD, AECOPD and comorbidities of COPD with the goal of identifying novel therapeutic targets. This review highlights the mouse models used to define the cellular, molecular and pathological consequences of cigarette smoke exposure and the recent advances in modelling infectious exacerbations and comorbidities of COPD. Copyright © 2015. Published by Elsevier B.V.
    Full-text · Article · Mar 2015 · European journal of pharmacology
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    • "We have demonstrated that Nrf2 is a negative regulator of cardiac pathological remodeling and dysfunction via suppressing oxidative stress in diverse pathological settings [6, 7]. While it has been documented that Nrf2 plays a mediator role in hydrogen sulfide-mediated suppression of oxidative stress-induced cardiac dysfunction [8], we and others have demonstrated that Nrf2 might be a drug target for the treatment of cardiomyocyte injury and cardiac dysfunction [9, 10]. Of interest, a recent report has revealed that Nrf2 is able to enhance autophagic clearance of toxic ubiquitinated protein aggregates secondary to ROS formation, suggesting a novel mediator role of Nrf2 for sufficient activation of autophagy [11]. "
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    ABSTRACT: The anticancer therapy of doxorubicin (Dox) has been limited by its acute and chronic cardiotoxicity. In addition to a causative role of oxidative stress, autophagy appears to play an important role in the regulation of Dox-induced cardiotoxicity. However, the underlying mechanisms remain unclear. Accordingly, we explored a role of nuclear factor erythroid-2 related factor 2 (Nrf2) in Dox-induced cardiomyopathy with a focus on myocardial oxidative stress and autophagic activity. In wild type (WT) mice, a single intraperitoneal injection of 25 mg/kg Dox rapidly induced cardiomyocyte necrosis and cardiac dysfunction, which were associated with oxidative stress, impaired autophagy, and accumulated polyubiquitinated protein aggregates. However, these Dox-induced adverse effects were exaggerated in Nrf2 knockout (Nrf2(-/-)) mice. In cultured cardiomyocytes, overexpression of Nrf2 increased the steady levels of LC3-II, ameliorated Dox-induced impairment of autophagic flux and accumulation of ubiquitinated protein aggregates, and suppressed Dox-induced cytotoxicity, whereas knockdown of Nrf2 exerted opposite effects. Moreover, the exaggerated adverse effects in Dox-intoxicated Nrf2 depleted cardiomyocytes were dramatically attenuated by forced activation of autophagy via overexpression of autophagy related gene 5 (Atg5). Thus, these results suggest that Nrf2 is likely an endogenous suppressor of Dox-induced cardiotoxicity by controlling both oxidative stress and autophagy in the heart.
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    • "Presently, pharmacological approaches that target single redox or ROS pathways (N-acetylcysteine, EGCG, Tocopherol) have shown mixed results in reducing the pathogenic progression of the muscular dystrophies (Scheuerbrandt, 2008), though combinatorial approaches may have better outcomes (Potgieter et al., 2011). In other diseases, genetic or pharmacological activation of Nrf2 has been shown to reduce oxidative and nitrosative stress and provide significant functional benefit (Thimmulappa et al., 2007; Sussan et al., 2009; Blake et al., 2010). Our results support a centralized role of Nrf2 deficiency in the pathogenesis of dysferlinopathy. "
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    ABSTRACT: Oxidative stress is a critical disease modifier in the muscular dystrophies. Recently, we discovered a pathway by which mechanical stretch activates NADPH Oxidase 2 (Nox2) dependent ROS generation (X-ROS). Our work in dystrophic skeletal muscle revealed that X-ROS is excessive in dystrophin-deficient (mdx) skeletal muscle and contributes to muscle injury susceptibility, a hallmark of the dystrophic process. We also observed widespread alterations in the expression of genes associated with the X-ROS pathway and redox homeostasis in muscles from both Duchenne muscular dystrophy patients and mdx mice. As nuclear factor erythroid 2-related factor 2 (Nrf2) plays an essential role in the transcriptional regulation of genes involved in redox homeostasis, we hypothesized that Nrf2 deficiency may contribute to enhanced X-ROS signaling by reducing redox buffering. To directly test the effect of diminished Nrf2 activity, Nrf2 was genetically silenced in the A/J model of dysferlinopathy-a model with a mild histopathologic and functional phenotype. Nrf2-deficient A/J mice exhibited significant muscle-specific functional deficits, histopathologic abnormalities, and dramatically enhanced X-ROS compared to control A/J and WT mice, both with functional Nrf2. Having identified that reduced Nrf2 activity is a negative disease modifier, we propose that strategies targeting Nrf2 activation may address the generalized reduction in redox homeostasis to halt or slow dystrophic progression.
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