利拉鲁肽对糖尿病心肌病大鼠心功能及心肌代谢异常的改善作用
作者:
作者单位:

(中国医学科学院 北京协和医学院 心血管疾病国家重点实验室 国家心血管病中心 阜外医院心血管代谢中心,北京市 100037)

作者简介:

朱雅馨,硕士研究生,研究方向为糖脂代谢异常,E-mail:zhuyaxin131@163.com。

基金项目:

国家自然科学基金项目(82172334);北京协和医学院协和青年基金(3332018200)


Effect of liraglutide on cardiac dysfunction and myocardial metabolism abnormality in diabetic cardiomyopathy rats
Author:
Affiliation:

Chinese Academy of Medical Sciences Peking Union Medical College & State Key Laboratory of Cardiovascular Disease & National Center for Cardiovascular Diseases & Cardiometabolic Center, Fuwai Hospital, Beijing 100037, China)

  • 摘要
  • | |
  • 访问统计
  • |
  • 参考文献
  • |
  • 相似文献
  • |
  • 引证文献
  • |
    摘要:

    目的]研究利拉鲁肽对糖尿病心肌病(DCM)大鼠心肌代谢物及相关代谢通路的影响。 [方法]3周龄SPF级雄性SD大鼠60只,随机抽取10只作为正常对照组,其余均采用腹腔注射链脲佐菌素联合高糖高脂饮食法建立DCM大鼠模型。DCM造模成功大鼠36只,随机分为DCM模型组(DCM组)、低剂量利拉鲁肽治疗组(LL组)、高剂量利拉鲁肽治疗组(HL组),每组各12只。LL组(100 μg/kg)和HL组(200 μg/kg)分别给予利拉鲁肽腹腔注射,每日一次,干预12周后,经超声心动图检测心功能后麻醉处死大鼠,并取心脏组织进行代谢组学检测,筛选并富集与利拉鲁肽改善DCM大鼠心肌代谢可能有关的差异代谢物及相关通路。 [结果]超声结果显示,与正常对照组相比,DCM组左心室射血分数(LVEF)、左心室短轴缩短率(LVFS)显著降低,左心室舒张早期最大血流/二尖瓣心房收缩期最大血流比值(E/A)明显升高(P<0.05)。与DCM组相比,LL组和HL组大鼠LVEF、LVFS明显升高,E/A比值显著降低(P<0.05),提示LL组和HL组左心室收缩和舒张功能受损明显减轻。代谢组学检测共发现395种代谢物,其中DCM组与正常对照组、LL组与DCM组、HL组与DCM组各自富集出组间差异代谢物分别为239种、116种、187种,代谢通路分别为13条、6条、20条。以上三组共交集出关键差异代谢物29种,主要涉及3条代谢通路(P<0.05),包括胆碱代谢通路、咖啡因代谢通路以及缬氨酸、亮氨酸和异亮氨酸生物合成通路,其中胆碱代谢通路差异最为显著。 [结论]利拉鲁肽可明显改善DCM大鼠心功能及心肌代谢异常,其中胆碱代谢通路可能在利拉鲁肽改善心肌代谢保护心脏功能过程中起到关键作用。

    Abstract:

    Aim To study the effect of liraglutide on myocardial metabolites and related metabolic pathways in diabetic cardiomyopathy (DCM) rats. Methods Among 60 SPF male SD rats aged 3 weeks, 10 rats were randomly selected as normal control group (n=10), and the remaining 50 rats were established by peritoneal injection of streptozotocin combined with high-sugar and high-fat diet for DCM rat model. A total of 36 rats were successfully modeled for DCM and randomly divided into DCM model group (DCM group, n=12), low-dose liraglutide treatment group (LL group, n=12) and high-dose liraglutide treatment group (HL group, n=12). Rats in LL group (100 μg/kg) and HL group (200 μg/kg) were given intraperitoneal injection of liraglutide once a day. And after 12 weeks of intervention, the rats were killed under anesthesia after echocardiography to detect cardiac function, and the heart tissues were taken for metabolomics detection. The differential metabolites and related pathways that may be related to liraglutide improving myocardial metabolism in DCM rats were screened and enriched. Results Compared with normal control group, left ventricular ejection fraction (LVEF) and left ventricular fractional shortening (LVFS) in DCM group were significantly decreased, and the ratio of early to late diastolic mitralflow velocities (E/A) was significantly increased (P<0.05). Compared with DCM group, LVEF and LVFS in LL group and HL group were significantly increased, and E/A ratio was significantly decreased (P<0.05), suggesting that the impairment of left ventricular systolic and diastolic function in LL group and HL group was significantly alleviated. 395 metabolites were detected by metabolomics, among which 9,6 and 187 different metabolites and 3,6 and 20 metabolic pathways were enriched in DCM group and normal control group, LL group and DCM group, HL group and DCM group. In the above three groups, 29 key differential metabolites were identified related to 3 metabolic pathways including choline metabolic pathway, caffeine metabolic pathway and valine, leucine and isoleucine biosynthesis pathway, among which choline metabolic pathway had the most significant differences. Conclusion These results indicated that liraglutide can ameliorate cardiac dysfunction in DCM rats through improving myocardial metabolism in which choline metabolism pathway may play a key role.

    参考文献
    [1] XI Y B, CHEN D, DONG Z, et al.Multi-omics insights into potential mechanism of SGLT2 inhibitors cardiovascular benefit in diabetic cardiomyopathy.Front Cardiovasc Med, 2,9:999254.
    [2] SUN J, XU J, LIU Y, et al.Proteomic and metabolomic analyses reveal the novel targets of spermine for alleviating diabetic cardiomyopathy in type Ⅱ diabetic mice.Front Cardiovasc Med, 2,9:1022861.
    [3] ZHANG Y W, ZHANG Z Y, LI C D, et al.Metabolomics study reveals the alteration of fatty acid oxidation in the hearts of diabetic mice by empagliflozin.Mol Omics, 2,8(7):643-651.
    [4] RITCHIE R H, ABEL E D.Basic mechanisms of diabetic heart disease.Circ Res, 0,6(11):1501-1525.
    [5] LI W, YAO M, WANG R, et al.Profile of cardiac lipid metabolism in STZ-induced diabetic mice.Lipids Health Dis, 8,7(1):231.
    [6] 蔡欢, 何玉秀, 刘静芹, 等.利拉鲁肽改善糖尿病心肌病大鼠心脏脂质异位沉积的效果和机制研究.中国循环杂志, 9,4(10):1013-1020.CAI H, HE Y X, LIU J Q, et al.Beneficial effects and mechanisms of liraglutide on improving cardiac ectopic lipid deposition and protecting cardiac function in diabetic cardiomyopathy rats.Chin Circ J, 9,4(10):1013-1020.
    [7] MARSO S P, DANIELS G H, BROWN-FRANDSEN K, et al.Liraglutide and cardiovascular outcomes in type 2 diabetes.N Engl J Med, 6,5(4):311-322.
    [8] DEC G W.Which drug will ‘Lead’ in reducing cardiac events among heart failure patients with diabetes?.J Am Coll Cardiol, 0,5(10):1142-1144.
    [9] TRANG N N, CHUNG C C, LEE T W, et al.Empagliflozin and liraglutide differentially modulate cardiac metabolism in diabetic cardiomyopathy in rats.Int J Mol Sci, 1,2(3):1177.
    [10] FAULKNER A, DANG Z X, AVOLIO E, et al.Multi-omics analysis of diabetic heart disease in the db/db model reveals potential targets for treatment by a longevity-associated gene.Cells, 0,9(5):1283.
    [11] SHAH A M, SHIN S H, TAKEUCHI M, et al.Left ventricular systolic and diastolic function, remodelling, and clinical outcomes among patients with diabetes following myocardial infarction and the influence of direct renin inhibition with aliskiren.Eur J Heart Fail, 2,4(2):185-192.
    [12] 周嘉琪, 林介夫, 陈嘉佳, 等.靶向CD36调控脂质代谢:糖尿病心肌病防治新靶点.中国动脉硬化杂志, 3,1(12):1013-1019.ZHOU J Q, LIN J F, CHEN J J, et al.Targeting CD36 to regulate lipid metabolism:a new strategy for the prevention and treatment of diabetic cardiomyopathy.Chin J Arterioscler, 3,1(12):1013-1019.
    [13] ZHAN J, JIN K, XIE R, et al.AGO2 protects against diabetic cardiomyopathy by activating mitochondrial gene translation.Circulation, 4,9(14):1102-1120.
    [14] MA X, MEI S, WUYUN Q, et al.Epigenetics in diabetic cardiomyopathy.Clin Epigenetics, 4,6(1):52.
    [15] LITWIN S E, RAYA T E, ANDERSON P G, et al.Abnormal cardiac function in the streptozotocin-diabetic rat.Changes in active and passive properties of the left ventricle.J Clin Invest, 0,6(2):481-488.
    [16] LIANG B, GU N.Liraglutide in the treatment of heart failure:insight from FIGHT and LIVE.Cardiovasc Diabetol, 0,9(1):106.
    [17] TAYANLOO-BEIK A, ROUDSARI P P, REZAEI-TAVIRANI M, et al.Diabetes and heart failure:multi-omicsapproaches.Front Physiol, 1,2:705424.
    [18] ZHAO L C, DONG M J, XU C C, et al.Identification of energy metabolism changes in diabetic cardiomyopathy rats using a metabonomic approach.Cell Physiol Biochem, 8,8(3):934-946.
    [19] DONG S, ZHANG R, LIANG Y, et al.Changes of myocardial lipidomics profiling in a rat model of diabetic cardiomyopathy using UPLC/Q-TOF/MS analysis.Diabetol Metab Syndr, 7,9:56.
    [20] HANG P Z, ZHAO J, SU Z L, et al.Choline inhibits ischemia-reperfusion-induced cardiomyocyte autophagy in rat myocardium by activating Akt/mTOR signaling.Cell Physiol Biochem, 8,5(5):2136-2144.
    [21] WANG Z N, KLIPFELL E, BENNETT B J, et al.Gut flora metabolism of phosphatidylcholine promotes cardiovascular disease.Nature, 1,2(7341):57-63.
    [22] CORR P B, CREER M H, YAMADA K A, et al.Prophylaxis of early ventricular fibrillation by inhibition of acylcarnitine accumulation.J Clin Invest, 9,3(3):927-936.
    [23] GROSS R W.Myocardial phospholipases A(2) and their membrane substrates.Trends Cardiovasc Med, 2,2(3):115-121.
    [24] MAKINO N, DHALLA K S, ELIMBAN V, et al.Sarcolemmal Ca2+ transport in streptozotocin-induced diabetic cardiomyopathy in rats.Am J Physiol, 7,3(2 Pt 1):E202-E207.
    [25] SYME C, CZAJKOWSKI S, SHIN J, et al.Glycerophosphocholine metabolites and cardiovascular disease risk factors in adolescents.Circulation, 6,4(21):1629-1636.
    引证文献
引用本文

朱雅馨,徐瑞霞,张月,渠惠琳,张薇,柳昊睿,王芳,郭远林,李建军.利拉鲁肽对糖尿病心肌病大鼠心功能及心肌代谢异常的改善作用[J].中国动脉硬化杂志,2024,32(6):494~502.

复制
分享
文章指标
  • 点击次数:96
  • 下载次数: 396
历史
  • 收稿日期:2024-01-22
  • 最后修改日期:2024-04-16
  • 在线发布日期: 2024-07-04