The protective role of liquiritin in high fructose-induced myocardial fibrosis via inhibiting NF-κB and MAPK signaling pathway

Abstract

Diabetic cardiomyopathy has been known as an important complication of diabetes and characterized by persistent diastolic dysfunction, resulting in myocardial fibrosis, which is associated inflammatory response and oxidative stress. Liquiritin is a major constituent of Glycyrrhiza Radix, possessing various pharmacological activities and exhibiting various positive biological effects, including anti-cancer, anti-oxidative and neuroprotective effects. Here, we investigated the anti-inflammatory properties and protective effects of lquiritin in high fructose-induced mice and cardiomyocytes to clarify the potential mechanism. The mice were divided into the control mice, 30% high fructose-induced mice, 10 mg/kg liquiritin-treaed mice after fructose feeding and 20 mg/kg liquiritin-treaed mice after fructose feeding. Liquiritin effectively reduced the lipid accumulation and insulin resistance induced by fructose feeding. In comparison to high fructose-feeding control mice, liquiritin-treated mice developed less myocardial fibrosis with lower expression of Collagen type I, Collagen type II and alpha smooth muscle-actin (α-SMA). In addition, liquiritin significantly reduced the inflammatory cytokine release and NF-κB phosphorylation through IKKα/IκBα signaling pathway suppression. Further, Mitogen-activated protein kinases (MAPKs), including p38, ERK1/2 and JNK, was up-regulated for fructose stimulation, which was inactivated by liquiritin treatment in vivo and in vitro studies. Our data indicates that liquiritin has a protective effect against high fructose-induced myocardial fibrosis via suppression of NF-κB and MAPKs signaling pathways, and liquiritin may be a promising candidate for diabetes-related myocardial fibrosis treatment.

Introduction

It has been a long time that diabetes is known as a major risk factor, contributing to cardiovascular disease [1]. Diabetes led to more than 70% patients death for cardiovascular disease, and would be a 200% increase in risk for cardiovascular death or two to three times the risk for death than non-diabetic population [2], [3]. Myocardial apoptosis, cardiomyocyte hypertrophy and interstitial fibrosis led to elasticity loss and diastolic myocardial systolic dysfunction have been the characteristic lesions for diabetic cardiomyopathy [4], [5]. Myocardial fibrosis, as a high mortality disease, it can not be explained by lesions mechanism of vascular heart disease, coronary artery disease, hypertensive heart disease, and other heart disease [6], [7]. Metabolic disorders caused by diabetic cardiomyopathy and microvascular disease could lead to a wide range of focal myocardial necrosis, subclinical cardiac dysfunction, and progress to heart failure ultimately, arrhythmias and cardiogenic shock, even death [8], [9]. Previous researches reported that there are a lot of abnormal collagen accumulation in the muscle fibers after the examination of patients with diabetes [10]. Also, the accumulation of collagen type III might happen to coronary heart disease related to type 2 diabetes through hypertension myocardial biopsy [11]. Recently, some studies indicated that myocardial interstitial fibrosis in diabetic cardiomyopathy may be earlier than the specific pathology [12], [13], [14].

In the last few decades, exploring the efficacy of natural compounds against various human metabolic diseases has caught attention among the scientific community [15], [16]. Compounds from plant belonging to different groups, including flavonoids, alkaloids, and polyphenols evaluated for their cancer preventive effects have yielded promising data, thus offering a potential therapeutic strategy against deadly disease [17], [18], [19]. Glycyrrhiza Radix has been used as a treatment for thousands of years in China and its major components have been reported to exhibit various pharmacological activities, including anti-inflammatory, anti-obesity, anti-viral, anti-oxidative and neuroprotective effects [20], [21], [22], [23]. Liquiritin, a major constituent of Glycyrrhiza Radix, possesses various pharmacological activities. Liquiritin also exerts neurotrophic effects, whereby it promotes nerve growth factor (NGF)-induced neurite outgrowth [24]. In addition, previous study has also reported that liquiritin may exert neuroprotective effects in cerebral ischemia/reperfusion-induced brain damage through antioxidant and anti-apoptotic mechanisms [25]. However, the protective effect of liquiritin against high fructose-induced myocardial fibrosis has not yet been elucidated.

Therefore, here fructose was administrated to mice to induce myocardial fibrosis in mice with diabetes and then the model mice were treated with different concentrations of liquiritin. Then the lipid metabolism and inflammation response via NF-κB and MAPKs signaling pathway respectively, were evaluated to clarify the role of liquiritin in myocardial fibrosis, providing a new therapeutic strategy for diabetic cardiomyopathy.