The Nuclear Factor Erythroid 2–Related Factor 2 Activator Oltipraz Attenuates Chronic Hypoxia–Induced Cardiopulmonary Alterations in Mice

Abstract

Nuclear factor erythroid 2-related factor 2 (Nrf2) is a key regulator that activates many antioxidant enzymes. Oxidative stress, which accumulates in diseased lungs associated with pulmonary hypertension (PH), is thought to be responsible for the progression of cardiopulmonary changes. To test whether Nrf2 activation would exert therapeutic efficacy against cardiopulmonary changes in a hypoxia-induced PH model, wild-type (WT) and Nrf2-deficient mice as well as Kelch-like ECH associating protein 1 (Keap1) (negative regulator of Nrf2) knockdown mutant mice were exposed to hypobaric hypoxia for 3 weeks. This chronic hypoxia exacerbated right ventricular systolic pressure, right ventricular hypertrophy (RVH), and pulmonary vascular remodeling in the WT mice. These pathological changes were associated with aberrant accumulation of Tenascin-C, a disease-indicative extracellular glycoprotein. Simultaneous administration of oltipraz, a potent Nrf2 activator, significantly attenuated RVH and pulmonary vascular remodeling and concomitantly ameliorated Tenascin-C accumulation in the hypoxic mice. Hypoxia-exposed Nrf2-deficient mice developed more pronounced RVH than WT mice, whereas hypoxia-exposed Keap1-knockdown mice showed less RVH and pulmonary vascular remodeling than WT mice, underscoring the beneficial potency of Nrf2 activity against PH. We also demonstrated that expression of the Nrf2-regulated antioxidant enzymes was decreased in a patient with chronic obstructive pulmonary disease associated with PH. The decreased antioxidant enzymes may underlie the pathogenesis of cardiopulmonary changes in the patient with chronic obstructive pulmonary disease and PH. The pharmacologically or genetically induced Nrf2 activity clearly decreased RVH and pulmonary vascular remodeling in the hypoxic PH model. The efficacy of oltipraz highlights a promising therapeutic potency of Nrf2 activators for the prevention of PH in patients with hypoxemic lung disease.

Basigin Mediates Pulmonary Hypertension by Promoting Inflammation and Vascular Smooth Muscle Cell Proliferation

“…Third, Bsg +/-VSMCs exhibited increased expression of nuclear factor E2-related factor-2 and heme oxygenase-1, which inhibit hypoxia-induced PH. 40,41 Consistently, in Bsg +/-VSMCs, proliferation of VSMCs was inhibited and integrin expression and secretion of growth factors were also inhibited in response to extracellular CyPA and hypoxia. Thus, extracellular CyPA and vascular Bsg cooperatively stimulate recruitment of inflammatory cells to the vessel wall, exacerbating perivascular inflammation and VSMC proliferation.…”

Oleanolic acid attenuates obstructive cholestasis in bile duct-ligated mice, possibly via activation of NRF2-MRPs and FXR antagonism

“…Moreover, recent studies have shown that the NRF2 activators such as UDCA and oltipraz induced MRP efflux transporters in rodent liver (Eba et al, 2013;Okada et al, 2008;Weerachayaphorn et al, 2014), and NRF2 binds to AREs at -9919 bp in the mouse MRP3 gene and to AREs/antioxidant response-like elements a t -3753 to -3767 bp in the mouse MRP4 gene (Maher et al, 2007). In this study, BDL caused intrinsic activation of NRF2 in mice as an adaptive response, however, this adaption was not potent in fully preventing cholestatic liver injury as demonstrated by marked liver pathological alteration and upregulation of multiple serum and liver biochemicals.…”

The Crossroads of Iron with Hypoxia and Cellular Metabolism. Implications in the Pathobiology of Pulmonary Hypertension

“…Heme interacts directly with Bach1, a transcriptional repressor, to deactivate it and allow for transcription of a multitude of genes in the metabolism of heme, including HO-1 (71). An additional mechanism includes heme-mediated stabilization of the transcription factor NF-E2-related factor 2 (Nrf2), a potent regulator of antioxidant proteins for which there is experimental evidence suggesting a protective effect in pulmonary vascular disease (72). This tightly regulated program likely serves as a protective mechanism in periods of high oxidant stress.…”