Original articleUrsolic acid ameliorates oxidative stress, inflammation and fibrosis in diabetic cardiomyopathy rats
Graphical abstract
Introduction
Diabetes mellitus, a group of chronic and metabolic disease, has becoming one of the greatest public health emergencies [1]. It is predicted that there will be 642 million people worldwide suffering from diabetes by 2040 [2]. Cardiovascular complications are the principal reasons of morbidity and mortality among diabetic patients, including atherosclerosis, myocardial infarction and cardiomyopathy [3]. Diabetic cardiomyopathy (DCM), refers to structural and functional impairments in the heart of diabetics, is the leading cause of heart failure [4], [5]. As a specific myocardial pathology, diabetic cardiomyopathy is independent of hypertension, coronary arteriosclerosis and other comorbidity [6], [7]. The pathophysiological mechanisms of diabetic cardiomyopathy are multifactorial, substantial evidences from both animal models and clinical data indicate that oxidative stress, increased cardiac inflammation and changes in the composition of extracellular matrix with enhanced cardiac fibrosis contribute to the development of diabetic cardiomyopathy [8]. Oxidative stress-induced cardiac inflammation and fibrosis are inextricably linked in diabetic cardiomyopathy [9]. Therefore, anti-oxidation, anti-inflammatory and anti-fibrotic strategies may provide new therapeutic approaches for combating diabetic cardiomyopathy [10].
Chinese herbal medicine has been widely used for thousands of years in the treatment of diabetic mellitus. Ursolic acid (UA, C30H48O3, molecular weight: 456.68), a pentacyclic triterpenoid compound, is naturally occurring in food products such as apples, basil, as well as in more than 120 plant species such as Mirabilis jalapa, and Ligustrum lucidum Ait, many of these are used as medicinal plants in traditional formulations [11]. UA possesses a wide range of biological properties including anti-tumor, anti-obesity, lowering blood glucose, anti-oxidation, anti-inflammation, anti-fibrosis, anti-atherosis, and has the therapeutic effect on many diseases [12], [13]. Most researches of UA focused on cancer, inflammatory diseases, diabetes and diabetic complications such as diabetic nephropathy [14]. Our previous study showed a preliminary cardioprotective effect of UA on alloxan-induced diabetic cardiomyopathy mice by attenuating cardiac fibrosis [15]. However, the mechanisms of UA in diabetic cardiomyopathy have not heretofore been lucubrated. Our current study aimed to further investigate the effects of UA on oxidative stress, inflammation and fibrosis and with the goal of proposing a novel therapeutic approach for the treatment of diabetic cardiomyopathy.
Section snippets
Animals and chemicals
Male Sprague-Dawley (SD) rats (8 weeks old weighing approximately 200–220 g) were obtained from Zhejiang Academy of Medical Sciences (License No. SCXK 2008-0033). Rats were housed in an air-conditioned room at 22 ± 2 °C with a lighting schedule of 12 h light and 12 h dark. Standard chow and tap water were available ad libitum. STZ was purchased from Sigma Chemical Co. (Sigma-Aldrich, MO, USA). STZ was more than 98% purity tested by high performance liquid chromatography (HPLC) and dissolved in 0.1 M
Effect of ursolic acid on hemodynamics
Systolic and diastolic function were severely compromised in diabetic rats (Fig. 1), with LVSP decreasing by 40.3% (P < 0.01) and LV + dp/dtmax by 47.9% (P < 0.01). Further, LVEDP was elevated by 251.5% (P < 0.01) and LV-dp/dtmax was lowered by 53.1% (P < 0.01) as compared to control rats. Importantly, with UA treatment apparently improved the systolic and diastolic function of the left ventricle in diabetic rats, as shown by decreased LVEDP by 63.6% (P < 0.01), and increased LV + dp/dtmax by 85.3% (P <
Discussion
Diabetic cardiomyopathy is one of the common complications in diabetic patients characterized by left ventricular dysfunction, cardiomyocyte hypertrophy and interstitial fibrosis [16], [17]. We found that using STZ-induced diabetic rat model provides typical disorder features that are relevant to diabetic cardiomyopathy, including increased levels of HWI, FBG, CK, LDH, as well as cardiac oxidative damage, inflammation and interstitial fibrosis; this confirms what has been reported in previous
Conflict of interest statement
The authors declare no conflicts of interest.
Acknowledgments
We are grateful for the grant by a project supported by Zhejiang Provincial Natural Science Foundation of China (Grant No: LY16H280013), associate chief technician You-fa Zhu (Zhejiang University) provided technical assistance in conducting the project.
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The two authors contributed equally to this work.