Pharmacological preconditioning with resveratrol:: role of CREB-dependent Bcl-2 signaling via adenosine A3 receptor activation
Pharmacological preconditioning with resveratrol:: role of CREB-dependent Bcl-2 signaling via adenosine A3 receptor activation
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DOI：
10.1152/ajpheart.00453.2004
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发表时间：
2005-01-01
影响因子：
4.8
通讯作者：
Das, DK
中科院分区：
文献类型：
--
作者：
Das, S;Cordis, GA;Das, DK
最近的研究表明，白藜芦醇是一种来自葡萄的多酚植物抗凝蛋白，通过一种非依赖机制提供心脏的药理预适应(PC)。由于腺苷受体在PC中起作用，我们研究了它们在白藜芦醇PC中是否起作用。将大鼠随机分为三组：1)Krebs-Henseleit碳酸氢盐缓冲液(KHB)；2)含10 MU白藜芦醇的KHB；3)10 MU白藜芦醇+1 MU 8-环戊基-1，3-二甲基黄嘌呤(CPT；腺苷A(1)受体阻断剂)；4)10 MU白藜芦醇+1 MU 8-(3-氯苯乙烯)咖啡因(CSC；腺苷A(2a)受体阻滞剂)；5)10 MU白藜芦醇+1 MU 3-ethyl-5-benzyl-2-methyl-4-phenylethynyl-6-phenyl-1，4-(+/-)-dihydropyridine-3，5-dicarboxylate(MRS-1191；腺苷A(3)受体阻滞剂)；或6)10 MU白藜芦醇+3 MU 2-(4-morpholinyl)-8-phenyl-1(4H)-benzopyran-4-one盐酸盐[LY-294002，磷脂酰肌醇(PI)3-激酶抑制剂]，以及仅灌流腺苷受体阻滞剂的组。然后心脏进行30分钟的缺血，然后再灌注2小时。结果表明，白藜芦醇具有显著的心脏保护作用，可促进心室恢复，减少心肌梗死面积和心肌细胞凋亡。CPT和MRS 1191，而不是CSC，取消了白藜芦醇的心脏保护能力，提示腺苷A(1)和A(3)受体在白藜芦醇PC中起作用。白藜芦醇诱导Bc l-2表达并使其磷酸化，同时使cAMP反应元件结合蛋白(CREB)、Akt和Bad磷酸化。CPT阻断Akt和Bad的磷酸化而不影响CREB，而MRS 1191阻断所有化合物的磷酸化，包括CREB。LY-294002可部分阻断白藜芦醇的心脏保护作用。结果表明，白藜芦醇通过激活腺苷A(1)和A(3)受体对心脏进行预调节，前者通过PI3-Kinase-AktBcl2信号通路传递生存信号，后者除Akt-Bcl2途径外，还通过依赖CREB的Bcl2途径保护心脏。
Recent studies demonstrated that resveratrol, a grape-derived polyphenolic phytoalexin, provides pharmacological preconditioning ( PC) of the heart through a NO-dependent mechanism. Because adenosine receptors play a role in PC, we examined whether they play any role in resveratrol PC. Rats were randomly assigned to groups perfused for 15 min with 1) Krebs-Henseleit bicarbonate buffer (KHB) only; 2) KHB containing 10 muM resveratrol; 3) 10 muM resveratrol + 1 muM 8-cyclopentyl-1,3-dimethylxanthine (CPT; adenosine A(1) receptor blocker); 4) 10 muM resveratrol + 1 muM 8-(3-chlorostyryl)caffeine (CSC; adenosine A(2a) receptor blocker); 5) 10 muM resveratrol + 1 muM 3-ethyl-5-benzyl-2-methyl-4-phenylethynyl-6-phenyl-1,4-(+/-)-dihydropyridine-3,5-dicarboxylate (MRS-1191; adenosine A(3) receptor blocker); or 6) 10 muM resveratrol + 3 muM 2-(4-morpholinyl)-8-phenyl-1(4H)-benzopyran-4-one hydrochloride [LY-294002, phosphatidylinositol (PI) 3-kinase inhibitor], and groups perfused with adenosine receptor blockers alone. Hearts were then subjected to 30-min ischemia followed by 2-h reperfusion. The results demonstrated significant cardioprotection with resveratrol evidenced by improved ventricular recovery and reduced infarct size and cardiomyocyte apoptosis. CPT and MRS 1191, but not CSC, abrogated the cardioprotective abilities of resveratrol, suggesting a role of adenosine A(1) and A(3) receptors in resveratrol PC. Resveratrol induced expression of Bcl-2 and caused its phosphorylation along with phosphorylation of cAMP response element-binding protein (CREB), Akt, and Bad. CPT blocked phosphorylation of Akt and Bad without affecting CREB, whereas MRS 1191 blocked phosphorylation of all compounds, including CREB. LY-294002 partially blocked the cardioprotective abilities of resveratrol. The results indicate that resveratrol preconditions the heart through activation of adenosine A(1) and A(3) receptors, the former transmitting a survival signal through PI3-kinase-AktBcl-2 signaling pathway and the latter protecting the heart through a CREB-dependent Bcl-2 pathway in addition to an Akt-Bcl-2 pathway.