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.

• Authors: Shunsuke Eba, Yasushi Hoshikawa, Takashi Moriguchi, Yoichiro Mitsuishi, Hironori Satoh, Kazuyuki Ishida, Tatsuaki Watanabe, Toru Shimizu, Hiroaki Shimokawa, Yoshinori Okada, Masayuki Yamamoto, Takashi Kondo
• Journal: American journal of respiratory cell and molecular biology (Am J Respir Cell Mol Biol) Vol. 49 Issue 2 Pg. 324-33 (Aug 2013) ISSN: 1535-4989 [Electronic] United States
• PMID: 23590302 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Adaptor Proteins, Signal Transducing
• Anticarcinogenic Agents
• Cytoskeletal Proteins
• Keap1 protein, mouse
• Kelch-Like ECH-Associated Protein 1
• NF-E2-Related Factor 2
• NFE2L2 protein, human
• Nfe2l2 protein, mouse
• Pyrazines
• Tenascin
• Thiones
• Thiophenes
• oltipraz

Topics

• Adaptor Proteins, Signal Transducing (genetics, metabolism)
• Animals
• Anticarcinogenic Agents (pharmacology)
• Cytoskeletal Proteins (genetics, metabolism)
• Disease Models, Animal
• Humans
• Hypertension, Pulmonary (drug therapy, etiology, genetics, metabolism, pathology)
• Hypertrophy, Right Ventricular (drug therapy, etiology, genetics, metabolism, pathology)
• Hypoxia (complications, drug therapy, genetics, metabolism, pathology)
• Kelch-Like ECH-Associated Protein 1
• Mice
• Mice, Knockout
• NF-E2-Related Factor 2 (genetics, metabolism)
• Pulmonary Disease, Chronic Obstructive (drug therapy, genetics, metabolism, pathology)
• Pyrazines (pharmacology)
• Tenascin (metabolism)
• Thiones
• Thiophenes