Pepducin-mediated cardioprotection via β-arrestin-biased β2-adrenergic receptor-specific signaling.
Pepducin-mediated cardioprotection via β-arrestin-biased β2-adrenergic receptor-specific signaling.
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DOI：
10.7150/thno.26619
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发表时间：
2018
期刊：
影响因子：
12.4
通讯作者：
Tilley DG
中科院分区：
文献类型：
--
作者：
Grisanti LA;Thomas TP;Carter RL;de Lucia C;Gao E;Koch WJ;Benovic JL;Tilley DG
再灌注作为急性心肌梗死引起的心脏损伤的治疗干预，其本身会诱导进一步的心肌细胞死亡。 β-抑制蛋白 (βarr) 偏向的 β-肾上腺素能受体 (βAR) 激活可促进体外生存信号反应；因此，我们假设该途径可以减轻再灌注时心肌细胞的死亡，以更好地保留功能。然而，由于缺乏有效的偏向βarr的正位小分子，阻碍了对该途径是否在体内传递针对缺血性损伤的保护作用的研究。我们最近证明，pepducin ICL1-9（一种由 β2AR 第一个细胞内环设计的小脂化肽片段）在体外以 βarr 依赖性方式变构参与促生存信号级联。因此，在本研究中，我们测试了 ICL1-9 是否能对缺血/再灌注 (I/R) 诱导的体内损伤发挥心脏保护作用。方法：野生型 (WT) C57BL/6、β2AR 敲除 (KO)、βarr1KO 和 βarr2KO 小鼠在缺血时（30 分钟）接受 ICL1-9 或乱序对照 pepducin (Scr) 心内注射，然后再灌注 24 小时，以评估梗死面积和心肌细胞死亡，或再灌注 4 周，以监测梗死面积和心肌细胞死亡的影响。 ICL1-9 对长期心脏结构和功能的影响。使用新生大鼠心室肌细胞 (NRVM) 来评估 ICL1-9 与 Scr pepducin 对心肌细胞存活和线粒体超氧化物形成的影响，以响应体外血清剥夺或缺氧/复氧 (H/R)，并研究相关机制。结果：I/R 时心肌内注射 ICL1-9 以 β2AR 和 βarr 依赖性方式减少梗塞面积、心肌细胞死亡并改善心脏功能，从而导致早期收缩功能改善并随着时间的推移减少纤维化重塑。从机制上讲，ICL1-9 以 RhoA/ROCK 依赖性方式减弱线粒体超氧化物的产生并促进心肌细胞存活。治疗后 24 小时内，可以在心肌细胞和整个心脏中检测到 RhoA 激活，这证明了 ICL1-9 对 βarr 依赖性 β2AR 信号传导作用的稳定性。结论：基于 Pepducin 的 βarr 依赖性 β2AR 信号转导变构调节代表了一种减少再灌注引起的心脏损伤并延续长期心脏重塑益处的新治疗方法。
Reperfusion as a therapeutic intervention for acute myocardial infarction-induced cardiac injury itself induces further cardiomyocyte death. β-arrestin (βarr)-biased β-adrenergic receptor (βAR) activation promotes survival signaling responses in vitro; thus, we hypothesize that this pathway can mitigate cardiomyocyte death at the time of reperfusion to better preserve function. However, a lack of efficacious βarr-biased orthosteric small molecules has prevented investigation into whether this pathway relays protection against ischemic injury in vivo. We recently demonstrated that the pepducin ICL1-9, a small lipidated peptide fragment designed from the first intracellular loop of β2AR, allosterically engaged pro-survival signaling cascades in a βarr-dependent manner in vitro. Thus, in this study we tested whether ICL1-9 relays cardioprotection against ischemia/reperfusion (I/R)-induced injury in vivo. Methods: Wild-type (WT) C57BL/6, β2AR knockout (KO), βarr1KO and βarr2KO mice received intracardiac injections of either ICL1-9 or a scrambled control pepducin (Scr) at the time of ischemia (30 min) followed by reperfusion for either 24 h, to assess infarct size and cardiomyocyte death, or 4 weeks, to monitor the impact of ICL1-9 on long-term cardiac structure and function. Neonatal rat ventricular myocytes (NRVM) were used to assess the impact of ICL1-9 versus Scr pepducin on cardiomyocyte survival and mitochondrial superoxide formation in response to either serum deprivation or hypoxia/reoxygenation (H/R) in vitro and to investigate the associated mechanism(s). Results: Intramyocardial injection of ICL1-9 at the time of I/R reduced infarct size, cardiomyocyte death and improved cardiac function in a β2AR- and βarr-dependent manner, which led to improved contractile function early and less fibrotic remodeling over time. Mechanistically, ICL1-9 attenuated mitochondrial superoxide production and promoted cardiomyocyte survival in a RhoA/ROCK-dependent manner. RhoA activation could be detected in cardiomyocytes and whole heart up to 24 h post-treatment, demonstrating the stability of ICL1-9 effects on βarr-dependent β2AR signaling. Conclusion: Pepducin-based allosteric modulation of βarr-dependent β2AR signaling represents a novel therapeutic approach to reduce reperfusion-induced cardiac injury and relay long-term cardiac remodeling benefits.
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影响因子：
3.9
作者：
Chen, Hao;Ma, Ning;Xu, Zhiwei
通讯作者：
Xu, Zhiwei
DOI：
10.1152/ajpheart.00755.2010
发表时间：
2011-11-01
影响因子：
4.8
作者：
Li, Xue;Mikhalkova, Deana;Chan, Tung O.
通讯作者：
Chan, Tung O.
影响因子：
7.3
作者：
Nobles KN;Xiao K;Ahn S;Shukla AK;Lam CM;Rajagopal S;Strachan RT;Huang TY;Bressler EA;Hara MR;Shenoy SK;Gygi SP;Lefkowitz RJ
通讯作者：
Lefkowitz RJ
DOI：
10.1161/atvbaha.115.306777
发表时间：
2016-01
期刊：
Arteriosclerosis, thrombosis, and vascular biology
影响因子：
--
作者：
Gurbel PA;Bliden KP;Turner SE;Tantry US;Gesheff MG;Barr TP;Covic L;Kuliopulos A
通讯作者：
Kuliopulos A
DOI：
10.1161/atvbaha.112.251769
发表时间：
2012-08
期刊：
Arteriosclerosis, thrombosis, and vascular biology
影响因子：
--
作者：
Bhushan S;Kondo K;Predmore BL;Zlatopolsky M;King AL;Pearce C;Huang H;Tao YX;Condit ME;Lefer DJ
通讯作者：
Lefer DJ