Scholarlink

<p>Myocardial infarction necessitates rapid reperfusion to limit ischemic damage. However, reperfusion itself exacerbates cardiomyocyte death and the inflammatory response. ATP release through pannexin1 (Panx1) channels is a key driver of leukocyte recruitment, yet most Panx1 channel inhibitors lack specificity or in vivo stability. We previously developed a macrocyclic peptidomimetic targeting the first extracellular loop (EL1) of Panx1, SBL-PX1-42, which demonstrated anti-inflammatory activity and high plasma stability in vitro. Here, we generated EL2 peptidomimetics, identified SBL-PX1-213 as a lead compound, and assessed its cardioprotective potential alone or combined with SBL-PX1-42 in experimental cardiac ischemia/reperfusion (I/R). In Langendorff-perfused wild-type (WT) hearts, SBL-PX1-42, SBL-PX1-213, and their combination did not affect baseline cardiac function, indicating absence of cardiotoxicity. In vivo I/R, induced by transient (30&#xa0;min) coronary artery ligation and 24&#xa0;h reperfusion, was performed in WT and <i>Panx1</i><sup><i>−/−</i></sup> mice. Intravenous administration of either compound at reperfusion reduced infarct size in WT animals. In <i>Panx1</i><sup><i>−/−</i></sup> mice, SBL-PX1-213 and the combination remained cardioprotective, whereas SBL-PX1-42 lost efficacy, supporting its Panx1-dependent activity. None of the treatments affected blood cell counts, suggesting the absence of unwanted side effects on circulating cells. These findings establish SBL-PX1-42 and SBL-PX1-213 as cardioprotective agents acting through both Panx1-dependent and Panx1-independent mechanisms.</p>

错误：搜索内容不能为空，请输入英文关键词
错误：关键词超出字数限制，请精简
高级检索

Pannexin1-dependent and -independent protection by novel peptidomimetics against cardiac ischemia/reperfusion injury

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2026年7月11日

查看全文
  • Malaury Tournier,
  • Arthur Lamouroux,
  • Laureano E. Carpio,
  • Viviane Bes,
  • Debora Iaculli,
  • Maral Azam,
  • Mathieu Vinken,
  • Rafael Gozalbes,
  • Filippo Molica,
  • Steven Ballet,
  • Brenda R. Kwak

摘要

Myocardial infarction necessitates rapid reperfusion to limit ischemic damage. However, reperfusion itself exacerbates cardiomyocyte death and the inflammatory response. ATP release through pannexin1 (Panx1) channels is a key driver of leukocyte recruitment, yet most Panx1 channel inhibitors lack specificity or in vivo stability. We previously developed a macrocyclic peptidomimetic targeting the first extracellular loop (EL1) of Panx1, SBL-PX1-42, which demonstrated anti-inflammatory activity and high plasma stability in vitro. Here, we generated EL2 peptidomimetics, identified SBL-PX1-213 as a lead compound, and assessed its cardioprotective potential alone or combined with SBL-PX1-42 in experimental cardiac ischemia/reperfusion (I/R). In Langendorff-perfused wild-type (WT) hearts, SBL-PX1-42, SBL-PX1-213, and their combination did not affect baseline cardiac function, indicating absence of cardiotoxicity. In vivo I/R, induced by transient (30 min) coronary artery ligation and 24 h reperfusion, was performed in WT and Panx1−/− mice. Intravenous administration of either compound at reperfusion reduced infarct size in WT animals. In Panx1−/− mice, SBL-PX1-213 and the combination remained cardioprotective, whereas SBL-PX1-42 lost efficacy, supporting its Panx1-dependent activity. None of the treatments affected blood cell counts, suggesting the absence of unwanted side effects on circulating cells. These findings establish SBL-PX1-42 and SBL-PX1-213 as cardioprotective agents acting through both Panx1-dependent and Panx1-independent mechanisms.