Abstract
Inflammation and oxidative stress plays an important role in the development of obesity‐related complications and cardiovascular disease. Benzimidazole and imidazopyridine compounds are a class of compounds with a variety of activities, including anti‐inflammatory, antioxidant and anti‐cancer. X22 is an imidazopyridine derivative we synthesized and evaluated previously for anti‐inflammatory activity in lipopolysaccharide‐stimulated macrophages. However, its ability to alleviate obesity‐induced heart injury via its anti‐inflammatory actions was unclear. This study was designed to evaluate the cardioprotective effects of X22 using cell culture studies and a high‐fat diet rat model. We observed that palmitic acid treatment in cardiac‐derived H9c2 cells induced a significant increase in reactive oxygen species, inflammation, apoptosis, fibrosis and hypertrophy. All of these changes were inhibited by treatment with X22. Furthermore, oral administration of X22 suppressed high‐fat diet‐induced oxidative stress, inflammation, apoptosis, hypertrophy and fibrosis in rat heart tissues and decreased serum lipid concentration. We also found that the anti‐inflammatory and anti‐oxidative actions of X22 were associated with Nrf2 activation and nuclear factor‐kappaB (NF‐κB) inhibition, respectively, both in vitro and in vivo. The results of this study indicate that X22 may be a promising cardioprotective agent and that Nrf2 and NF‐κB may be important therapeutic targets for obesity‐related complications.
Highlights
In the past few decades, the prevalence of obesity has increased dramatically worldwide to become a global epidemic
We examined the mRNA expression of NF-jB-activated inflammatory cytokines, such as TNF-a, IL-1b and IL-6, and cell adhesion molecules, intercellular adhesion molecule 1 (ICAM-1) and vascular cell adhesion molecule 1 (VCAM-1)
We examined the effects of X22 in high-fat diet (HFD)-induced oxidative stress in rat myocardial tissues. 3-NT was used as a biomarker for formation of ROS and reactive nitrogen species (RNS)
Summary
In the past few decades, the prevalence of obesity has increased dramatically worldwide to become a global epidemic. Obesity has become increasingly characterized as an inflammatory state, as chronic low-grade inflammation and oxidative stress play important roles in the pathogenesis of obesity-related complications [9,10,11,12,13]. It is well known that circulating free fatty acids (FFAs) associated with obesity, including palmitic acid (PA), can cause chronic inflammation, insulin resistance and cardiovascular disease. Free fatty acids can increase the expression of pro-inflammatory cytokines and induce cellular oxidative stress, and it has been demonstrated that both in vitro and in vivo that FFAs can activate the nuclear factor-kappaB (NF-jB) pathway, subsequently increasing the expression of several pro-inflammatory cytokines such as tumour necrosis a 2016 The Authors
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