Evaluation of the role of Nrf2/Keap1 pathway-associated novel mutations and gene expression on antioxidant status in patients with deep vein thrombosis.

Deep vein thrombosis (DVT) is a type of venous thromboembolism and a clinically complex vascular disease. Oxidative stress serves a key role in the pathogenesis of numerous cardiovascular diseases, particularly in endothelial dysfunction-associated syndromes. Nuclear factor erythroid-2-like 2(Nrf2) transcription factor is the primary regulator of antioxidant responses. The levels of reactive oxygen species (ROS) are regulated by Nrf2 and its suppressor protein Kelch-like ECH-associated protein 1 (Keap1). However, to the best of our knowledge, genetic abnormalites in the Nrf2/Keap1 pathway in DVT syndrome have not been thoroughly investigated. The aim of the present study was to investigate the association between the Nrf2/Keap1 pathway and antioxidant responses in DVT. Mutations and expression levels of genes involved in the Nrf2/Keap1 pathway were measured in 27 patients with DVT via DNA sequencing analysis and reverse transcription-quantitative PCR, respectively. The Polymorphism Phenotyping v2 program was used to identify the pathogenic mutations. Total antioxidant activity levels were determined by measuring the effect of serum samples from 27 patients with DVT on oxidation of the 2,2'-azino-bis (3-ethylbenz-thiazoline-6-sulfonic acid) system. A total of 23 mutations, including seven novel mutations, were detected in the Nrf2/Keap1 pathway in 24 (89%) of the 27 patients with DVT. Keap1 mRNA expression levels were significantly higher compared with Nrf2 expression levels in patients with DVT (P=0.02). Analysis of molecular characteristics and gene expression levels demonstrated that Nrf2/Keap1-associated mutations and total antioxidant levels can be used as precursor markers in the diagnosis of DVT.

Effects of interventions on oxidative stress and inflammation of cardiovascular diseases.

Excessive oxidative stress and low-grade chronic inflammation are major pathophysiological factors contributing to the development of cardiovascular diseases (CVD) such as hypertension, diabetes and atherosclerosis. Accumulating evidence suggests that a compromised anti-oxidant system can lead to excessive oxidative stress in cardiovascular related organs, resulting in cell damage and death. In addition, increased circulating levels of pro-inflammatory cytokines, such as tumor necrosis factor α, interleukin-6 and C-reactive protein, are closely related to morbidity and mortality of cardiovascular complications. Emerging evidence suggests that interventions including nutrition, pharmacology and exercise may activate expression of cellular anti-oxidant systems via the nuclear factor erythroid 2-related factor 2-Kelch-like ECH-associated protein 1 signaling pathway and play a role in preventing inflammatory processes in CVD. The focus of the present review is to summarize recent evidence showing the role of these anti-oxidant and anti-inflammatory interventions in cardiovascular disease. We believe that these findings may prompt new effective pathogenesis-oriented interventions, based on the exercise-induced protection from disease in the cardiovascular system, aimed at targeting oxidant stress and inflammation.