Selective β2-adrenoreceptor stimulation attenuates myocardial cell death and preserves cardiac function after ischemia-reperfusion injury.
Selective β2-adrenoreceptor stimulation attenuates myocardial cell death and preserves cardiac function after ischemia-reperfusion injury.
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DOI：
10.1161/atvbaha.112.251769
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发表时间：
2012-08
期刊：
影响因子：
--
通讯作者：
Lefer DJ
中科院分区：
文献类型：
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作者：
Bhushan S;Kondo K;Predmore BL;Zlatopolsky M;King AL;Pearce C;Huang H;Tao YX;Condit ME;Lefer DJ
β2-肾上腺素受体激活已被证明可以保护心肌细胞免于细胞死亡。我们假设，使用阿福特罗 (ARF) 进行急性 β2-肾上腺素受体刺激，会通过 NO 合酶激活减轻心肌缺血/再灌注 (R) 损伤，并导致 NO 生物利用度随后增加。雄性 C57BL/6J 和内皮 NO 合酶 (eNOS) 敲除小鼠接受 45 分钟的心肌缺血和 24 小时的 R 治疗。在 R 治疗前 5 分钟给予 ARF 或载体。测量血清肌钙蛋白-I，并在 R 治疗 24 小时时评估每个危险区域的梗死面积。在基线和 R 治疗后 2 周进行超声心动图检查。心肌 cAMP、蛋白激酶 A，测定了 eNOS/Akt 磷酸化状态和 NO 代谢物水平。 ARF (1 μg/kg) 使每个危险区域的梗塞面积减少了 53.1%（与媒介物相比，P<0.001），并显着降低了肌钙蛋白-I 水平（与媒介物相比，P<0.001）。 R 治疗 2 周时，与载体心脏相比，ARF 处理的心脏的射血分数显着保留。注射 ARF 后 5 分钟和 15 分钟，血清 cAMP 和核蛋白激酶 A C-α 分别增加（P<0.01）。 ARF 增加了 Thr308 (P<0.001) 和 Ser473 (P<0.01) 处的 Akt 磷酸化，以及 Ser1177 处的 eNOS 磷酸化 (P<0.01)。注射后 15 分钟，ARF 治疗增加了心脏亚硝基硫醇水平 (P<0.001)。 ARF 未能减少 eNOS−/− 小鼠的梗塞面积。我们的结果表明，β2-肾上腺素受体刺激可激活 cAMP、蛋白激酶 A、Akt 和 eNOS，并增加 NO 生物利用度。这种促存活信号通路的激活可减轻心肌细胞死亡并在缺血/再灌注后保留心脏功能。
β2-adrenoreceptor activation has been shown to protect cardiac myocytes from cell death. We hypothesized that acute β2-adrenoreceptor stimulation, using arformoterol (ARF), would attenuate myocardial ischemia/reperfusion (R) injury via NO synthase activation and cause a subsequent increase in NO bioavailability. Male C57BL/6J and endothelial NO synthase (eNOS) knockout mice were subjected to 45 minutes of myocardial ischemia and 24 hours of R. ARF or vehicle was administered 5 minutes before R. Serum troponin-I was measured, and infarct size per area-at-risk was evaluated at 24 hours of R. Echocardiography was performed at baseline and 2 weeks after R. Myocardial cAMP, protein kinase A, eNOS/Akt phosphorylation status, and NO metabolite levels were assayed. ARF (1 μg/kg) reduced infarct size per area-at-risk by 53.1% (P<0.001 versus vehicle) and significantly reduced troponin-I levels (P<0.001 versus vehicle). Ejection fraction was significantly preserved in ARF-treated hearts compared with vehicle hearts at 2 weeks of R. Serum cAMP and nuclear protein kinase A C-α increased 5 and 15 minutes after ARF injection, respectively (P<0.01). ARF increased Akt phosphorylation at Thr308 (P<0.001) and Ser473 (P<0.01), and eNOS phosphorylation at Ser1177 (P<0.01). ARF treatment increased heart nitrosothiol levels (P<0.001) at 15 min after injection. ARF failed to reduce infarct size in eNOS−/− mice. Our results indicate that β2-adrenoreceptor stimulation activates cAMP, protein kinase A, Akt, and eNOS and augments NO bioavailability. Activation of this prosurvival signaling pathway attenuates myocardial cell death and preserves cardiac function after ischemia/reperfusion.