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<p>E-prostanoid 3 receptor (EP3) plays an important role in maintaining normal heart growth and development, and its activation may drive acute inflammation and influence intracellular Ca<sup>2+</sup> level. The effects of targeting EP3 on myocardial injury have been very controversial. We aimed to elucidate roles of EP3 in both innate immune cells and cardiomyocytes during the acute phase of acute myocardial injury. Wild-type, global <i>Ep3</i> knockout (<i>Ep3</i><sup>−/−</sup>), myeloid conditional <i>Ep3</i>-deficient (<i>Ep3</i><sup><i>F/F</i></sup><i>;Lyz2</i><sup><i>Cre</i></sup>) and tamoxifen-induced cardiomyocyte-specific <i>Ep3</i> knockout (<i>Ep3</i><sup><i>F/F</i></sup><i>;Myh6</i><sup><i>MerCreMer</i></sup>) mice were subjected to regional ischemia/reperfusion (I/R) or acute doxorubicin (DOX) treatment. Inflammation, prostaglandin production, and damage-associated molecular pattern (DAMP) release were induced in acute myocardial injury in mice and patients. Injury caused by I/R or DOX was substantially ameliorated in EP3 antagonist-treated wild-types, but not in their <i>Ep3</i><sup>−/−</sup> counterparts. I/R injury was alleviated in <i>Ep3</i><sup><i>F/F</i></sup><i>;Lyz2</i><sup><i>Cre</i></sup> rodents and <i>Ep3</i><sup><i>F/F</i></sup><i>;Myh6</i><sup><i>MerCreMer</i></sup> mice at 1&#xa0;week after the administration of tamoxifen, but exacerbated in the latter at 8&#xa0;weeks. Germline <i>Ep3</i><sup><i>−/−</i></sup> hearts were predisposed to abnormalities. Antagonism or myeloid deficiency of EP3 ameliorated I/R injury by suppressing inflammation and regulating necrosis pathways, constituting an auto-amplification loop of necroinflammation. EP3 disruption in cardiomyocytes prevented the agonist-induced increase of diastolic Ca<sup>2+</sup> level. Short-term EP3 abrogation in cardiomyocytes also reduced local and systemic inflammation after I/R. Collectively, long-term EP3 abrogation predisposes hearts to abnormalities and is detrimental; however, its deficiency in myeloid cells or transient deletion in cardiomyocytes convergently mitigates necroinflammation and alleviates acute myocardial injury, indicating short-term EP3 blockade is a potentially promising therapeutic strategy for such diseases.</p>

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Short-term blockade of E-prostanoid 3 receptor mitigates necroinflammation and ameliorates ischemia/reperfusion- and doxorubicin-induced acute myocardial injury

  • 期刊论文

  • 发表日期：

    2026年3月17日

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  • Dong He,
  • Yequn Chen,
  • Jiahui Ge,
  • Jinwei Guo,
  • Zhen Wang,
  • Gang Yu,
  • Shiwan Wu,
  • Jing Leng,
  • Bin Wang,
  • Shunyu Pang,
  • Xijian Chen,
  • Yineng Xu,
  • Cheng Peng,
  • Jianye Yang,
  • Shijun Liu,
  • Anhong Cai,
  • Zhengpeng Zeng,
  • Xinya Shi,
  • Siyi Ling,
  • Yukuan Chen,
  • Yingbi Zhou,
  • Bin Liu

摘要

E-prostanoid 3 receptor (EP3) plays an important role in maintaining normal heart growth and development, and its activation may drive acute inflammation and influence intracellular Ca2+ level. The effects of targeting EP3 on myocardial injury have been very controversial. We aimed to elucidate roles of EP3 in both innate immune cells and cardiomyocytes during the acute phase of acute myocardial injury. Wild-type, global Ep3 knockout (Ep3−/−), myeloid conditional Ep3-deficient (Ep3F/F;Lyz2Cre) and tamoxifen-induced cardiomyocyte-specific Ep3 knockout (Ep3F/F;Myh6MerCreMer) mice were subjected to regional ischemia/reperfusion (I/R) or acute doxorubicin (DOX) treatment. Inflammation, prostaglandin production, and damage-associated molecular pattern (DAMP) release were induced in acute myocardial injury in mice and patients. Injury caused by I/R or DOX was substantially ameliorated in EP3 antagonist-treated wild-types, but not in their Ep3−/− counterparts. I/R injury was alleviated in Ep3F/F;Lyz2Cre rodents and Ep3F/F;Myh6MerCreMer mice at 1 week after the administration of tamoxifen, but exacerbated in the latter at 8 weeks. Germline Ep3−/− hearts were predisposed to abnormalities. Antagonism or myeloid deficiency of EP3 ameliorated I/R injury by suppressing inflammation and regulating necrosis pathways, constituting an auto-amplification loop of necroinflammation. EP3 disruption in cardiomyocytes prevented the agonist-induced increase of diastolic Ca2+ level. Short-term EP3 abrogation in cardiomyocytes also reduced local and systemic inflammation after I/R. Collectively, long-term EP3 abrogation predisposes hearts to abnormalities and is detrimental; however, its deficiency in myeloid cells or transient deletion in cardiomyocytes convergently mitigates necroinflammation and alleviates acute myocardial injury, indicating short-term EP3 blockade is a potentially promising therapeutic strategy for such diseases.