目的 探讨黄精多糖（Polygonatum sibiricum polysaccharide,PSP）对低压低氧大鼠心肌能量代谢的改善作用并探讨其机制。方法 将24只Wistar大鼠随机分为对照组（control）、低压低氧组（HH）和低压低氧+PSP组（HH+PSP）,每组8只。HH组和HH+PSP组大鼠在低压氧舱模拟海拔 6000 m进行慢性低压低氧干预2 w,HH+PSP组灌胃给予 PSP 400 mg/kg,其余两组灌胃给予等体积生理盐水。每周检测2次体重、2次摄食量,处死前超声心动图检测各组大鼠心功能指标,测定大鼠血清及心肌组织中游离脂肪酸( free fatty acids, FFA)、葡萄糖(glucose, GLU)、乙酰辅酶A（acetyl coenzyme A, A-CoA）以及三磷酸腺苷（adenosine triphosphate , ATP）含量评价能量代谢情况,Western blotting检测大鼠心肌组织过氧化物酶体增殖物激活受体α（peroxisome proliferator activated receptor alpha,PPARα）、肉碱棕榈酰转移酶1（carnitine palmitoyltransferase 1,CPT-1）、丙酮酸脱氢酶4（pyruvate dehydrogenase kinase 4,PDK4）、葡萄糖转运蛋白4（glucose transporter,GLUT4）、甘油醛-3-磷酸脱氢酶（glyceraldehyde-3-phosphate dehydrogenase,GAPDH）的表达水平。结果 与对照组相比,HH组大鼠体重和摄食量显著降低(P<0.05);超声心动图显示心输出量、心室末期容积及每搏输出量均降低(P<0.05),心室后壁厚度显著增高(P<0.05);能量代谢相关指标检测显示GLU、ATP显著降低(P<0.05),FFA、A-CoA含量显著升高(P<0.05);Western blotting结果显示心肌组织PPARα、CPT-1、PDK4表达水平显著降低（P<0.05）,GLUT4、GAPDH的表达显著升高（P<0.05）。与HH组相比,HH+PSP组大鼠体重及摄食量无显著变化(P>0.05);心输出量、心室末期容积、心室后壁厚度及每搏输出量均得到显著改善(P<0.05);GLU、ATP含量显著升高(P<0.05),FFA、A-CoA含量显著降低(P<0.05)。此外,PPARα、CPT-1、PDK4、GLUT4、GAPDH的蛋白表达水平也得到显著下调（P<0.05）。结论 低压低氧暴露导致大鼠心功能损伤与能量代谢紊乱密切相关,PSP干预可以显著缓解低压低氧暴露导致的大鼠心肌能量代谢水平变化,并显著改善心功能损伤,可能与调控心肌组织PPARα- CPT-1/PDK4、GLUT4、GAPDH表达相关。
Abstract
Objective To investigate the regulatory effect of Polygonatum sibiricum polysaccharides (PSP) on myocardial energy metabolism in hypobaric hypoxia exposed rats and explore its mechanism. Methods Twenty-four Wistar rats were randomly divided into control group (control), hypobaric hypoxia group (HH) and hypobaric hypoxia+PSP group (HH+PSP) with eight rats in each group. Rats in the HH and HH + PSP groups were subjected to chronic HH exposure for 2 weeks in a hypobaric chamber at a simulated altitude of 6000m. The HH+PSP group was given 400mg/ kg PSP and the other two groups were given equal volume of saline. The body weight and food intake were measured twice a week, and cardiac function was measured by echocardiography at the end of the experiment. Determination of free fatty acids (FFA), glucose (GLU), acetyl coenzyme A (A-CoA) and adenosine triphosphate (ATP) in serum and myocardial tissues was carried out to evaluate energy metabolism. The expression levels of peroxisome proliferator activated receptor alpha (PPARα), carnitine palmitoyltransferase 1(CPT-1), pyruvate dehydrogenase kinase 4 (PDK4), glucose transporter (GLUT4) and glyceraldehyde- 3-phosphate dehydrogenase (GAPDH) in rat myocardial tissue were examined by Western blotting. Results Compared with control group, rats in the HH group had significantly lower body weight and food intake (P<0.05). Echocardiography showed lower cardiac output, ventricular end volume and stroke volume (P<0.05),while ventricular posterior wall thickness was significantly higher. Energy metabolism-related indexes showed significantly lower GLU and ATP (P<0.05), and significantly higher FFA and A-CoA contents (P<0.05). Western blotting of myocardial tissue proteins showed significantly decreased expression levels of PPARα, CPT-1, PDK4 (P<0.05) and significantly increased expression levels of GLUT4 and GAPDH (P<0.05). Compared with the HH group, there were no significant changes in body weight and food intake in the HH+PSP group (P>0.05).Cardiac output, ventricular end volume and stroke volume were improved (P<0.05), and ventricular posterior wall thickness was decreased (P<0.05). GLU and ATP levels were significantly increased (P<0.05), and FFA and A-CoA levels were significantly decreased (P<0.05). PPARα, CPT-1, PDK4, GLUT4 and GAPDH protein expression levels were significantly down-regulated (P<0.05). Conclusion Cardiac malfunction caused by HH exposure is closely related to the disturbance of energy metabolism in rats. The intervention of PSP can significantly improve myocardial energy metabolism and cardiac function after HH exposure, which may be related to the changes of the expression of PPARα-CPT-1 /PDK4, GLUT4 and GAPDH in myocardial tissues.
关键词
低压低氧 /
黄精多糖 /
心肌损伤 /
能量代谢
Key words
hypobaric hypoxia /
Polygonatum sibiricum polysaccharide /
myocardial injury /
energy metabolism
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参考文献
[1] Wasyluk W, Nowicka-Stążka P, Zwolak A.Heart metabolism in sepsis-induced cardiomyopathy-unusual metabolic dysfunction of the heart[J]. Int J Environ Res Public Health, 2021,18:7598.
[2] Neely JR, Rovetto MJ, Oram JF.Myocardial utilization of carbohydrate and lipids[J]. Prog Cardiovasc Dis, 1972,15:289–329.
[3] van Berlo JH, Maillet M, Molkentin JD. Signaling effectors underlying pathologic growth and remodeling of the heart[J]. J Clin Invest, 2013,123:37–45.
[4] Murray AJ.Energy metabolism and the high-altitude environment[J]. Exp Physiol, 2016,101:23–27.
[5] 唐萍, 朱艳, 孟文潮, 等. 黄精多糖的提取方法及活性研究进展[J].山东化工,2023,52:70–72.
[6] Wang Y, Qin S, Pen G, et al. Original Research: potential ocular protection and dynamic observation of Poly-gonatum sibiricum polysaccharide against streptozocin-induced diabetic rats' model[J]. Exp Biol Med (Maywood), 2017,242:92–101.
[7] Xie Y, Jiang Z, Yang R, et al. Polysaccharide-rich extract from Polygonatum sibiricum protects hemato-poiesis in bone marrow suppressed by triple negative breast cancer[J]. Biomed Pharmacother, 2021,137:111338.
[8] 陆紫楠, 金晨钟, 胡一鸿, 等. 黄精多糖药食同源作用及其研究进展[J].现代食品,2023,29:72–74.
[9] Palmer BF, Clegg DJ.Ascent to altitude as a weight loss method: the good and bad of hypoxia inducible factor activation[J]. Obesity (Silver Spring), 2014,22:311–317.
[10] Genovese A, De Alfieri W, Latte S, et al. Regression of myocardial hypertrophy in the rat following removal of acute or chronic hypobaric hypoxia[J]. Eur Heart J, 1982,3(Suppl A):161–164.
[11] Azzouzi HE, Leptidis S, Doevendans PA, et al. HypoxamiRs: regulators of cardiac hypoxia and energy metabolism[J]. Trends Endocrinol Metab, 2015,26:502–508.
[12] Mustafa Rizvi SH, Shao D, Tsukahara Y, et al. Oxidized GAPDH transfers S-glutathionylation to a nuclear protein Sirtuin-1 leading to apoptosis[J]. Free Radic Biol Med, 2021,174:73–83.
[13] Rajabi M, Kassiotis C, Razeghi P, et al. Return to the fetal gene program protects the stressed heart: a strong hypothesis[J]. Heart Fail Rev, 2007,12:331–343.
[14] Arumugam S, Sreedhar R, Thandavarayan RA, et al. Targeting fatty acid metabolism in heart failure: is it a suitable therapeutic approach?[J]. Drug Discov Today, 2016,21:1003–1008.
[15] Korvald C, Elvenes OP, Myrmel T.Myocardial substrate metabolism influences left ventricular energetics in vivo[J]. Am J Physiol Heart Circ Physiol, 2000,278:H1345–351.
[16] Dyck JR, Cheng JF, Stanley WC, et al. Malonyl coenzyme a decarboxylase inhibition protects the ischemic heart by inhibiting fatty acid oxidation and stimulating glucose oxidation[J]. Circ Res, 2004,94:e78–84.
[17] Yan J, Song K, Bai Z, et al. WY14643 improves left ventricular myocardial mitochondrial and systolic functions in obese rats under chronic persistent hypoxia via the PPARα pathway[J]. Life Sci, 2021,266:118888.
[18] Bonnefont JP, Djouadi F, Prip-Buus C, et al. Carnitine palmitoyltransferases 1 and 2: biochemical, molecular and medical aspects[J]. Mol Aspects Med, 2004,25:495–520.
[19] Olaniyi KS, Olatunji LA.Preventive effects of L-glutamine on gestational fructose-induced cardiac hypertrophy: involvement of pyruvate dehydrogenase kinase-4[J]. Appl Physiol Nutr Metab, 2019,44:1345–1354.
[20] Barger PM, Brandt JM, Leone TC, et al. Deactivation of peroxisome proliferator-activated receptor-alpha during cardiac hypertrophic growth[J]. J Clin Invest, 2000,105:1723–1730.
[21] Deng B, Liu W, Pu L, et al. Quantitative proteomics reveals the effects of resveratrol on high-altitude polycythemia treatment[J]. Proteomics, 2020,20: e1900423.
