Long-term stimulation of adenosine A2b receptors begun after myocardial infarction prevents cardiac remodeling in rats
Long-term stimulation of adenosine A2b receptors begun after myocardial infarction prevents cardiac remodeling in rats
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DOI：
10.1161/circulationaha.106.630087
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发表时间：
2006-10-31
期刊：
影响因子：
37.8
通讯作者：
Kitakaze, Masafumi
中科院分区：
文献类型：
--
作者：
Wakeno, Masakatsu;Minamino, Tetsuo;Kitakaze, Masafumi
腺苷抑制心脏成纤维细胞的增殖和心肌细胞的肥大，这两者在心脏重塑中起着至关重要的作用。在本研究中，我们调查是否慢性刺激腺苷受体开始后，心肌梗死（MI）防止心脏remodeling.Methods和结果- MI在Wistar大鼠永久结扎左冠状动脉前降支。MI发作后1周，将动物随机分为8组：赋形剂组、双嘧达莫组、（DIP;腺苷摄取抑制剂，50 mg/kg），2-chroloadenosine（CADO;腺苷的稳定类似物，2 mg/ kg）和CADO，在非选择性腺苷受体拮抗剂8-磺苯基茶碱（8-SPT）或腺苷A1、A2 a、A2 b的选择性拮抗剂存在下，或A3受体。治疗3周后，DIP和CADO组的血流动力学和超声心动图参数与溶剂组相比显著改善。这些血流动力学和超声心动图的改善被8-SPT或选择性腺苷A2 b拮抗剂MRS 1754所减弱，但不被其他腺苷受体亚型的选择性拮抗剂所减弱。与载体组相比，DIP和CADO组的胶原体积分数更小，并且与心脏重塑相关的分子如非梗死区域中的基质金属蛋白酶的基因表达减少，8-SPT或MRS 1754均能使其减弱。心肌梗死后开始的腺苷A2 b受体的长期刺激可减轻非梗死心肌的心脏纤维化并改善心脏功能。刺激腺苷A2 b受体或增加腺苷水平的药物是预防MI后心脏重塑的新候选药物。
Background - Adenosine inhibits proliferation of cardiac fibroblasts and hypertrophy of cardiomyocytes, both of which may play crucial roles in cardiac remodeling. In the present study, we investigated whether chronic stimulation of adenosine receptors begun after myocardial infarction ( MI) prevents cardiac remodeling.Methods and Results - MI was produced in Wistar rats by permanent ligation of the left anterior descending coronary artery. One week after the onset of MI, animals were randomized into 8 groups: vehicle, dipyridamole ( DIP; the adenosine uptake inhibitor, 50 mg/kg), 2-chroloadenosine ( CADO; the stable analogue of adenosine, 2 mg/ kg), and CADO in the presence of the nonselective adenosine receptor antagonist 8-sulfophenyltheophylline ( 8-SPT) or the selective antagonist for adenosine A1, A2a, A2b, or A3 receptor. Three weeks after treatment, hemodynamic and echocardiographic parameters in the DIP and CADO groups were significantly improved compared with the vehicle group. These hemodynamic and echocardiographic improvements were blunted by either 8-SPT or the selective adenosine A2b antagonist MRS1754 but not by the selective antagonists for other subtypes of adenosine receptors. The collagen volume fraction was smaller, and gene expression of the molecules associated with cardiac remodeling such as matrix metalloproteinase in noninfarcted areas was reduced in the DIP and CADO groups compared with the vehicle group, both of which were attenuated by either 8-SPT or MRS1754.Conclusions - Long-term stimulation of adenosine A2b receptors begun after MI attenuates cardiac fibrosis in the noninfarcted myocardium and improves cardiac function. Drugs that stimulate adenosine A2b receptors or increase adenosine levels are new candidates for preventing cardiac remodeling after MI.