| 1,140 | 9 | 14 |
| 下载次数 | 被引频次 | 阅读次数 |
目的：探究姜黄素对糖尿病心肌病小鼠的保护作用及对SIRT3/FOXO3a信号通路的影响。方法：将20只C57 BL/6小鼠随机分为正常对照组（Con组）、模型组（DCM组）、低剂量姜黄素组（LC组）、高剂量姜黄素组（HC组），除正常对照组外，其余各组均采用高脂高糖喂养联合腹腔注射链脲佐菌素（60 mg/kg）建立糖尿病心肌病模型。模型建立成功后，干预组分别予以高剂量（200 mg·kg-1·d-1）、低剂量（100 mg·kg-1·d-1）姜黄素灌胃，Con组、DCM组予以生理盐水灌胃。连续用药12周后行超声心动图检查测量小鼠心肌结构及功能变化，HE染色观察小鼠心肌组织病理表现；TUNEL法检测各组小鼠心肌细胞凋亡情况；检测心肌组织中脂质过氧化物丙二醛（MDA）的含量、超氧化物歧化酶（SOD）和谷胱甘肽过氧化物酶（GSH-Px）的活性，DCFH-DA检测细胞内ROS水平；荧光定量PCR检测SIRT3、FOXO3a通路mRNA表达情况，Western blot法检测SIRT3、FOXO3a、Bcl2、Bax、Cleaved caspase-3蛋白表达。结果：与DCM组相比，姜黄素干预后，心脏彩超提示各项指标均有改善（P<0.05）,TUNEL凋亡染色显示，凋亡率明显下降（P<0.05）,HE染色提示细胞水肿，排列紊乱等变化明显改善，SIRT3、FOXO3a、Bcl2表达增加，Bax、Cleaved caspase-3表达减少，SOD、GSH-Px活性明显升高（P<0.05）,MDA及ROS水平明显降低（P<0.05）。结论：姜黄素对糖尿病心肌病小鼠具有心肌保护及抑制心肌重塑的作用，该作用机制可能与激活SIRT3/FOXO3a信号通路相关。
Abstract：Objective: To investigate the protective effect of curcumin on mice with diabetic cardiomyopathy and its effect on SIRT3/FOXO3a signaling pathway. Methods: A total of twenty C57BL/6 mice were randomly assigned to four groups, with five mice in each group: the normal control group(Con group), the model group [diabetic cardiomyopathy(DCM) group], the lowdose curcumin group(LC group), and the high-dose curcumin group(HC group). Except for the Con group, the mice in other groups were fed with high-fat and high-glucose diet combined with intraperitoneal injection of streptozotocin(60 mg/kg) to establish the DCM model. After the model was effectively established, the intervention group received high-dose(200 mg·kg-1·d-1) and low-dose(100 mg·kg-1·d-1) curcumin administration via gavage, while the Con group and DCM group received normal saline administration via gavage. Following 12 weeks of uninterrupted medication, echocardiography was conducted to assess the myocardial structure and function, and HE staining was performed to observe the pathological manifestations of myocardial tissue. The TUNEL method was utilized to identify apoptosis in mouse cardiomyocytes within each group. The levels of lipid peroxidemalondial, superoxide dismutase, and glutathione peroxidase(GSH-Px) activities in myocardial tissue were assessed, while intracellular ROS levels were measured using DCFH-DA. The expression of mRNA in the SIRT3 and FOXO3a pathways was determined through fluorescence PCR, and the expression of SIRT3, FOXO3a, Bcl2, Bax, and Cleaved caspase-3 proteins was examined using the Western blot method. Results: In comparison to the DCM group, following curcumin intervention, all the indices demonstrated amelioration in cardiac ultrasound(P<0.05). TUNEL apoptosis staining revealed a significant reduction in the rate of apoptosis(P<0.05). Additionally, HE staining exhibited notable improvement in cellular edema, disorder in arrangement, the expression of SIRT3, FOXO3a, and Bcl2 was enhanced, while the expression of Bax and Cleaved caspase-3 was diminished. Moreover, the activity of superoxide dismutase and GSH-Px exhibited a significant increase(P<0.05), whereas the levels of lipid peroxidemalondial and ROS were notably decreased(P<0.05). Conclusion: Curcumin has myocardial protective effect and inhibition of ventricular remodeling in mice with diabetic cardiomyopathy, and the mechanism of action may be related to the activation of SIRT3/FOXO3a signaling pathway.
1 Cole JB, Florez JC. Genetics of diabetes mellitus and diabetes complications[J]. Nat Rev Nephrol, 2020,16(7):377-390.
2 Tan Y, Zhang Z, Zheng C, et al. Mechanisms of diabetic cardiomyopathy and potential therapeutic strategies:Preclinical and clinical evidence[J]. Nat Rev Cardiol,2020,17(9):585-607.
3 Alizadeh M, Kheirouri S. Curcumin against advanced glycation end products(AGEs)and AGEs-induced detrimental agents[J]. Crit Rev Food Sci Nutr, 2019,59(7):1169-1177.
4 Kane AE, Sinclair DA. Sirtuins and NAD(+)in the development and treatment of metabolic and cardiovascular diseases[J]. Circ Res, 2018,123(7):868-885.
5 Sundaresan NR, Gupta M, Kim G, et al. Sirt3 blocks the cardiac hypertrophic response by augmenting Foxo3adependent antioxidant defense mechanisms in mice[J]. J Clin Invest, 2009,119(9):2758-2771.
6 Li H, Sureda A, Devkota HP, et al. Curcumin, the golden spice in treating cardiovascular diseases[J]. Biotechnol Adv, 2020,38 107343.
7 Zheng Y, Ley SH, Hu FB. Global aetiology and epidemiology of type 2 diabetes mellitus and its complications[J]. Nat Rev Endocrinol, 2018,14(2):88-98.
8 Cai L, Kang YJ. Oxidative stress and diabetic cardiomyopathy:a brief review[J]. Cardiovasc Toxicol, 2001,1(3):181-193.
9 Peng ML, Fu Y, Wu CW, et al. Signaling pathways related to oxidative stress in diabetic cardiomyopathy[J].Front Endocrinol(Lausanne), 2022,13:907757.
10 Qiu J, Liu D, Li P, et al. NADPH oxidase mediates oxidative stress and ventricular remodeling through SIRT3/FOXO3a pathway in diabetic mice[J]. Antioxidants(Basel), 2022,11(9):1745.
11 Zheng J, Cheng J, Zheng S, et al. Curcumin, A polyphenolic curcuminoid with its protective effects and molecular mechanisms in diabetes and diabetic cardiomyopathy[J]. Front Pharmacol, 2018,9:472.
12 Ren BC, Zhang YF, Liu SS, et al. Curcumin alleviates oxidative stress and inhibits apoptosis in diabetic cardiomyopathy via Sirt1-Foxo1 and PI3K-Akt signalling pathways[J]. J Cell Mol Med, 2020,24(21):12355-12367.
13 Grabowska W, Sikora E, Bielak-Zmijewska A. Sirtuins, a promising target in slowing down the ageing process[J]. Biogerontology, 2017,18(4):447-476.
14 Koentges C, Pfeil K, Schnick T, et al. SIRT3 deficiency impairs mitochondrial and contractile function in the heart[J]. Basic Res Cardiol, 2015,110(4):36.
15 Zhang J, Ren D, Fedorova J, et al. SIRT1/SIRT3 modulates redox homeostasis during ischemia/reperfusion in the aging heart[J]. Antioxidants(Basel), 2020,9(9):858.
16 Chen J, Chen S, Zhang B, et al. SIRT3 as a potential therapeutic target for heart failure[J]. Pharmacol Res,2021,165:105432.
17 Cheng P, Zeng W, Li L, et al. PLGA-PNIPAM microspheres loaded with the gastrointestinal nutrient NaB ameliorate cardiac dysfunction by activating Sirt3 in acute myocardial infarction[J]. Adv Sci(Weinh), 2016,3(12):1600254.
18 Wang LF, Huang CC, Xiao YF, et al. CD38 deficiency protects heart from high fat diet-induced oxidative stress via activating Sirt3/FOXO3 pathway[J]. Cell Physiol Biochem, 2018,48(6):2350-2363.
19 Hu J, Liu T, Fu F, et al. Omentin1 ameliorates myocardial ischemia-induced heart failure via SIRT3/FOXO3adependent mitochondrial dynamical homeostasis and mitophagy[J]. J Transl Med, 2022,20(1):447.
20 Yu W, Gao B, Li N, et al. Sirt3 deficiency exacerbates diabetic cardiac dysfunction:Role of Foxo3A-Parkin-mediated mitophagy[J]. Biochim Biophys Acta Mol Basis Dis, 2017,1863(8):1973-1983.
基本信息:
DOI：10.13210/j.cnki.jhmu.20231129.003
中图分类号:R285.5
引用信息:
[1]李星,钟毅,陈雪.姜黄素通过调节SIRT3/FOXO3a通路改善糖尿病心肌病的机制研究[J].海南医学院学报,2024,30(06):401-406.DOI:10.13210/j.cnki.jhmu.20231129.003.
基金信息:
泸州市人民政府-西南医科大学战略合作项目（2018-LZXNYD ZK48）~~
2024-01-02
2024-01-02
2024-01-02