Center for Preclinical Investigation, Fondazione IRCCS Ospedale Maggiore Policlinico, Mangiagalli e Regina Elena, Milano, Italy.
Peptides. 2010 Jan;31(1):116-22. doi: 10.1016/j.peptides.2009.09.030. Epub 2009 Sep 30.
alpha-Melanocyte-stimulating hormone (alpha-MSH) is a pro-opiomelanocortin (POMC)-derived peptide that exerts multiple protective effects on host cells. Previous investigations showed that treatment with alpha-MSH or synthetic melanocortin agonists reduces heart damage in reperfusion injury and transplantation. The aim of this preclinical research was to determine whether melanocortin treatment induces preconditioning-like cardioprotection. In particular, the plan was to assess whether melanocortin administration causes phenotype changes similar to those induced by repetitive ischemic events. The idea was conceived because both ischemic preconditioning and melanocortin signaling largely depend on cAMP response element binding protein (CREB) phosphorylation. Rats received single i.v. injections of 750microg/kg of the alpha-MSH analogue Nle(4),DPhe(7)-alpha-MSH (NDP-MSH) or saline and were sacrificed at 0.5, 1, 3, or 5h. Western blot analysis showed that rat hearts expressed melanocortin 1 receptor (MC1R) protein. Treatment with NDP-MSH was associated with early and marked increase in interleukin 6 (IL-6) mRNA. This was followed by signal transducer and activator of transcription 3 (STAT3) phosphorylation and induction of suppressor of cytokine signaling 3 (SOCS3). There were no changes in expression of other cytokines of the IL-6 family. Expression of IL-10, IL-1beta, and TNF-alpha was likewise unaltered. In hearts of rats treated with NDP-MSH there was increased expression of the orphan nuclear receptor Nur77. The data indicate that NDP-MSH induces phenotype changes that closely resemble ischemic preconditioning and likely contribute to its established protection against reperfusion injury. In addition, the increased expression of Nur77 and SOCS3 could be part of a broader anti-inflammatory effect.
α-黑素细胞刺激素（alpha-MSH）是一种前阿黑皮素原（POMC）衍生的肽，对宿主细胞具有多种保护作用。先前的研究表明，α-MSH 或合成的黑皮质素激动剂治疗可减轻再灌注损伤和移植中的心脏损伤。本临床前研究的目的是确定黑素皮质素治疗是否诱导类似预处理的心脏保护作用。特别是，计划评估黑素皮质素给药是否引起类似于重复缺血事件诱导的表型变化。这个想法的产生是因为缺血预处理和黑素皮质素信号传导在很大程度上依赖于 cAMP 反应元件结合蛋白（CREB）磷酸化。大鼠接受 750μg/kg 的α-MSH 类似物 Nle（4），DPhe（7）-α-MSH（NDP-MSH）或生理盐水的单次静脉内注射，并在 0.5、1、3 或 5 小时处死。Western blot 分析显示大鼠心脏表达黑素皮质素 1 受体（MC1R）蛋白。NDP-MSH 治疗与白细胞介素 6（IL-6）mRNA 的早期和明显增加有关。随后是信号转导和转录激活因子 3（STAT3）磷酸化和抑制细胞因子信号 3（SOCS3）的诱导。IL-6 家族的其他细胞因子表达没有变化。IL-10、IL-1β和 TNF-α的表达也没有改变。在接受 NDP-MSH 治疗的大鼠心脏中，孤儿核受体 Nur77 的表达增加。数据表明，NDP-MSH 诱导的表型变化与缺血预处理非常相似，可能有助于其对再灌注损伤的既定保护作用。此外，Nur77 和 SOCS3 的表达增加可能是更广泛的抗炎作用的一部分。
