Elsevier

Biomedicine & Pharmacotherapy

Volume 89, May 2017, Pages 991-1004
Biomedicine & Pharmacotherapy

Bixin ameliorates high fat diet-induced cardiac injury in mice through inflammation and oxidative stress suppression

https://doi.org/10.1016/j.biopha.2017.02.052Get rights and content

Abstract

Diabetic cardiomyopathy is known as an essential complication of diabetes, a main reason leading to mortality for diabetic patients, and novel therapeutic strategies for treatment are urgently required. Bixin (BX), isolated from the seeds of Bixa orellana, is a carotenoid, possessing anti-inflammatory, anti-tumor and anti-oxidant activities. In our study, we attempted to calculate the role of bixin in cardiac injury progression, and reveal the possible molecular mechanism. Bixin treatment ameliorated cardiac dysfunction through inhibiting fibrosis, inflammation and reactive oxygen species (ROS) generation. It reduced fibrosis levels via collagen deposition down-regulation. Inflammatory response was attenuated by reducing pro-inflammatory cytokines secretion via Toll-like receptor 4/nuclear factor kappa B (TLR4/NF-κB) signaling pathway inactivation in mice induced by high fat diet. Also, in in vitro studies, lipopolysaccharide (LPS)-treated cardiac muscle cells exhibits pro-inflammatory cytokines over-expression, which was reduced by bixin through blocking TLR4/NF-κB pathway. Additionally, oxidative stress triggered by high fat in vivo and LPS in vitro was down-regulated for bixin administration via nuclear factor-E2-related factor 2 (Nrf2) signaling pathway activation. Our study suggested that bixin might be a novel and protective agent with therapeutic activity against cardiac injury by suppressing fibrosis, inflammation and oxidative stress.

Introduction

Diabetic cardiomyopathy is known as one of the most common complications for diabetes and also as a main reason for the mortality to diabetic patients at accumulated risk for cardiovascular diseases development [1], [2]. Additionally, obesity is known as a global disease, which is related to cardiovascular diseases, including cardiomyocyte hypertrophy and cardiac fibrosis [3], [4]. Obesity has been well reported as an important reason, leading to diabetes and metabolic syndrome in animals, which is closely associated with cardiovascular diseases progression [5], [6]. Obesity promotes cardiovascular disease via many mechanisms including ectopic lipid deposition, hyperglycemia, and the development of a procoagulant state [7], [8], [9]. Though, a lot of evidences indicated the possible molecular mechanisms and therapeutic strategies, the specific pathophysiology of obesity-associated cardiac injury is still complex, regarding to apoptosis, fibrosis, inflammation and oxidative stress, and novel treatments are still needed to be investigated [10], [11]. Thus, here in our study, we attempted to establish obesity animal model via high fat diet feeding for a consecutive long time according to previous studies to induce cardiac injury [12]. Bixin, isolated from the seeds of Bixa orellana, is a carotenoid. The carotenoid bixin (BX) may reduce inflammatory response and oxidative damage [13]. Previous studies have indicated that bixin consumption could be an adjuvant to prevent atherosclerosis by reducing oxidative damage, inflammatory response and dyslipidemia [14], [15]. Thus, our study is aimed to explore if bixin could be also used as an effective therapeutic strategy for improving cardiac injury and to reveal the underlying molecular mechanism.

Previous studies have indicated that long time exposure to high fat diet feeding could lead to fibrosis development in liver and also in heart [16], [17]. Fibrosis, including the cardiac, is a disease with a lot of abnormal collagen accumulation in the muscle fibers through activating α-SMA, collagen type I and collagen type III [18], [19]. Additionally, fibrosis progression has a close relationship with inflammation response [20]. Further, the toll-like receptor 4 (TLR4) is one of the pattern recognition receptors, playing an important role in the inflammatory response induction and activating the down-streaming signaling, including nuclear factor kappa B (NF-κB) [21]. Activation of TLR4 leads to the expression of NF-κB dependent pro-inflammatory cytokines, such as interleukin 1β (IL-1β), interleukin 18 (IL-18) and tumor necrosis factor-α (TNF-α) [22], [23]. It is reported that high-fat diet results in hyperlipidemia, and up-regulates the concentration of lipopolysaccharide (LPS) in serum, which is a stimulator for TLR4 activation [24]. Thus, blocking excessive TLR4 expression is an available therapeutic strategy for cardiac injury treatment in order to inhibit inflammation induced by high fat diet, which might be a possible molecular mechanism indicating the effects of bixin on treating cardiac injury.

Oxidative stress has been well investigated in various diseases, leading to cells damage via diverse mechanisms [25], [26]. Oxidative stress could be induced by many external stresses, including irradiation, ultraviolet light, and ischemia/reperfusion [27]. As previously reported, high fat diet is also a typical stress, leading to reactive oxygen species (ROS) accumulation through disrupting the balance of oxidants and anti-oxidants [28]. For instance, during the process of oxidative stress, anti-oxidant SOD, as well as ROS scavenger of nuclear factor-E2-related factor 2 (Nrf2) and HO-1, is expressed lowly [29], [30]. A large number of natural compounds, used in traditional medicine due to their anti-oxidant and anti-inflammatory properties, have been exhibited to induce Nrf2 expression, protecting against various types of stresses [31], [32]. Furthermore, oxidative stress has been reported in cardiac injury development under various situations, including high fat diet-induced obesity in animals [33], [34]. Therefore, we supposed that bixin might perform its role in ameliorating high fat diet-induced cardiac injury through ROS suppression in mice.

In our study, we investigated the role of bixin in cardiac injury induced by high fat diet in mice. We clearly indicated that bixin administration protect high fat diet-induced mice against cardiac fibrosis, inflammation and ROS generation through TLR4/NF-κB signaling pathway regulation and Nrf2-mediated ROS production in vivo and in vitro.

Section snippets

Animal models

Totally 80 male, 6–8 weeks, C57BL/6 mice weighed 20–25 g were purchased from the Experimental Animal Center of Shandong (Shandong, China). All animal experiments were performed to minimize animal suffering according to the Guide for the Care and Use of Laboratory Animals which was issued by the National Institutes of Health in 1996 (http://www.most.gov.cn). Before the experiments, all mice were housed in a specific pathogen-free, temperature and humidity-controlled environment (25 ± 2 °C, 50 ± 5%

Bixin restrained systemic metabolism disorder in high fat diet-induced mice

High fat diet-induced mice were treated with various concentrations of bixin in order to calculate the possibly protective effects on systemic metabolism disorder. As shown in Fig. 1B and C, the OGTT and ITT results indicated that insulin resistance was significantly observed in the experimental mice only treated with high fat diet. However, the insulin resistance in the groups treated with bixin was suppressed shown in a dose-dependent manner, which was comparable to the HFD group. And the

Discussion

Our study illustrated that bixin protected mice against cardiac injury induced by high fat diet in mouse model and in cardiac muscle cells. The protective role of bixin in suppressing cardiac injury is linked to reduction of collagen accumulation, inactivity of TLR4/NF-κB signaling pathway and down-regulation of ROS generation. ROS generation suppressed by bixin was related to Nrf2 expression, which was a major regulator for ROS production [29], [30], [31], [32]. The findings in our study

Competing financial interests

The authors declare no competing financial interests.

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      In terms of immunomodulatory or anti-inflammatory properties, few studies appear available concerning B. orellana crude plant extracts, and concern leaves (Lima Viana et al., 2018; Yong et al., 2018). Bixin however, the major natural carotenoid extracted from B. orellana seeds, is highlighted for its anti-inflammatory properties, notably in various in vivo models (Pacheco et al., 2019; Somacal et al., 2015; Xu and Kong, 2017). Many other carotenoids were also isolated from the seeds and could also account for the observed biological effect (Vilar et al., 2014).

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