目的 观察腺苷A1受体激活对异丙肾上腺素诱导的大鼠心肌肥厚的抑制作用,并观察心肌能量变化,从而探讨腺苷对心肌肥厚的能量调节作用及其相关机制。方法 皮下注射大剂量异丙肾上腺素建立大鼠心肌肥厚模型。SD大鼠40只,雌雄不限,随机分为4组:①空白对照组、②肥厚模型组、③CCPA组(2-氯环戊腺苷)、④普萘洛尔组,每组10只。造模结束第2天起连续给药8周,到期后处死大鼠并测定全心质量指数(HMI)和左心质量指数(LVMI);取左心组织后行HE染色,光镜下观察心肌细胞形态;测定大鼠心肌组织中游离脂肪酸(FFA)、乳酸(LAC)、ATP含量;Western blot技术检测转化生长因子(TGF)-β1、Smad3蛋白表达水平。结果 同模型组比较,CCPA组可以降低HMI、LVMI;降低FFA、LAC含量;升高ATP的含量,使TGF-β1、Smad3蛋白表达减少,且差别有统计学意义。结论 腺苷A1受体激活可以保护心肌,其机制可能与其能改善心肌肥厚的能量代谢,并且能够减少TGF-β1、Smad3蛋白的表达水平进而使TGF-β1/Smad3通路信号传导受到抑制有关。
Abstract
OBJECTIVE To observe the inhibitiory effect of adenosine A1 receptor stimulation on myocardial hypertrophy by TGF-β1/Smad3 signal pathways and myocardial energy metabolism in rats and discuss its related mechanism. METHODS High dose isoproterrnol was subcutaneously injected into rats to establish myocardial hypertrophy model. Forty Sprague-Dawley rats were randomly divided into four groups with ten rats for each group:blank control group,isoproterenol model group, CCPA(150 μg·kg-1·min-1) treatment group.From second day after modeling,rats in CCPA group and in propranolol group were injected continuosly for eight weeks. Then the heart mass index (HMI)and left ventricular mass index (LVMI) were measured, the myocardial cells were observed under the light microscope by HE staining. The free fatty acids (FFA), lactic acids (LAC) and adenosine triphosphate (ATP) contents in myocardial tissue of rats were detected. The relative expression of TGE-β1 and Smad3 protein were determined by Western blotting. RESULTS Compared with model group, in CCPA group, the HMI and LVMI were reduced, the conetent of FFA and LAC were decreased, the content of ATP was increased,and the relative expression of TGF-β1/Smad3 of CCPA group was decreased. CONCLUSION When the adenosine A1 receptor was stimulated, it can improve the energy metabolism of myocardial hypertrophy, and restrain TGF-β1/Smad3 signal pathway, thus it play a protective role in the myocardial cells by reducing the expression of TGF-β1 and Smad3 protein.
关键词
心肌肥厚 /
腺苷 /
异丙肾上腺素 /
TGF-β1/Smad3信号通路
{{custom_keyword}} /
Key words
myocardial hypertrophy /
adenosine /
isoproterenol /
TGF-β1/Smad3
{{custom_keyword}} /
中图分类号：
R965
{{custom_clc.code}}
({{custom_clc.text}})
{{custom_sec.title}}
{{custom_sec.title}}
{{custom_sec.content}}
参考文献
[1] MEYER T E, CHUNG E S, PERLINI S, et al. Antiadrenergic effects of adenosine in pressure overload hypertrophy[J] . J Hypertens, 2001, 37(3):862-868.
[2] HAN Y L,YANG Y H, WANG H X. Activation of adenosine A1 receptor inhibits glucose-induced cardiomyocyte hypertrophy[J] .Chin Pharmacol Bull(中国药理学通报),2010,26(4):531-535.
[3] LI Z Y, YANG Y H, XING L. Stimulation of adenosine A1 receptor attenuates angiotensin Ⅱ induced myocardial hypertrophy in neonatal rats via the extracellular signal-regulated kinase signal pathways[J] . Chin J Cardiol(中国心血管病杂志),2013, 41(8):698-703.
[4] XING L, YANG Y H, WANG H X, et al. Inhibition of activated adenosine A1 receptor to the myocardical hypertrophy induced by isoprenaline in neonatal rats by calcineurin signal pathways[J] . Chin Pharmacol Bull(中国药理学通报),2012,28(6):847-852.
[5] XING L, YANG Y H, WANG H X, et al. Cross-talk between adenosine A1 receptor and kappa-opioid receptor(κ-OR) activation on isoproterenol-induced cardiomyocyte hypertrophy[J] . Chin J Hypertens(中华高血压杂志), 2012, 33(1):50-56.
[6] LI L, WU L L, WANG C, et al. Adiponectin modulated carnitine palmitoyltransferase-1 through AMPK signaling cascade in rat cardiomyocytes[J] . Regul Pept,2007,139(1-3):72-79.
[7] GAO X, HE X, LUO B, et al. Angiotensin Ⅱ increases collagen I expression via transforming growth factor-beta1 and extracellular signal-regulated kinase in cardiac fibroblasts[J] . Eur J Pharmacol,2009,606(1-3):115-120.
[8] SUNDQVIST A, TEN DIJKE P, VAN DAM H. Key signaling nodes in mammary gland development and cancer:Smad signal integration in epithelial cell plasticity[J] . Breast Cancer Res,2012,14(1):204.
[9] RONA G, CHAPPEL C I, BALAZS T, et al. An infact-like myocardial lesion and other toxic manifestations produced by isoproterenol in the rat[J] . Arch Pathol Lab Med,1959,67(4):443-455.
[10] ROHINI A, AGRAWAL N, KOYANI C N, et al. Molecular targets and regulators of cardiac hypertrophy [J] . Pharmacol Res, 2010, 61(4): 269-280.
[11] HEIDRICH F, SCHOTOLA H, POPOV A F,et al. AMPK-activated protein kinase and its role in energy metabolism of the heart[J] . Curr Cardiol Rev, 2010, 6(4): 337-342.
[12] KOLWICZ S C J R, TIAN R. Glucose metabolism and cardiac hypertrophy[J] . Cardiovasc Res, 2011, 90(2): 194-201.
[13] ROSENKRANZ S. TGF-β1 and angiotensin networking in cardiac re-modeling[J] .Cardiovasc Res,2004,63(6): 423-432.
[14] PERRIER E, KERFANT B G, LALEVEE N, et al. Mineralocorticoid receptor antagonism prevents the electrical remodeling that precedes cellular hypertrophy after myocardial infarction[J] . Circulation,2004,110(7): 776-783.
[15] STRIDE N, LARSEN S, TREEBAK J T, et al. 5′-AMP activated protein kinase is involved in the regulation of myocardialβ-oxidative capacity in mice[J] .Front Physiol, 2012, 3: 33.
[16] LIU J, WANG P, HE L, et al. Cardiomyocyte-restricted deletion of PPARβ/δ in PPARα-null mice causes impaired mitochondrial biogenesis and defense,but no further depression of myocardial fatty acid oxidation [J] . PPAR Res,2011, 2011: 372854.
[17] LIU J, WANG P, LUO J, et al. Peroxisome proliferator-activated receptorβ/δ activation in adult hearts facilitates mitochondrial function and cardiac performance under pressure-overload condition [J] . Hypertension, 2011, 57(2): 223-230.
[18] WANG S, SONG P, ZOU M H. AMP-activated protein kinase, stress responses and cardiovascular diseases [J] . Clin Sci(Lond), 2012, 122(12): 555-573.
{{custom_fnGroup.title_cn}}
脚注
{{custom_fn.content}}
基金
河南省教育厅重点项目资助(14A320045);郑州大学第二附属医院人才培育基金资助
{{custom_fund}}
PDF(1239 KB)
