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<p>Vascular cell adhesion molecule 1 (VCAM-1), a known downstream target of the Forkhead box O (FoxO) family of transcription factors, has well-established roles in development, cell-cell interactions, and cell survival. However, the specific role and mechanisms whereby VCAM-1 governs cardiomyocyte homeostasis in ischemic heart disease are incompletely understood. Here, we report that ischemia/reperfusion (I/R)-induced myocardial damage resulted in marked attenuation of <i>FoxO1</i> and <i>Vcam1</i> mRNA levels in wild-type (WT) mice, suggesting a protective role of the FoxO1/VCAM-1 axis in I/R injury. Indeed, compared with WT littermates, cardiomyocyte-specific loss of <i>Vcam1</i> significantly exacerbated I/R-induced myocardial damage, apoptotic cardiomyocyte death, contractile dysfunction, and maladaptive cardiac remodeling. We go on to show that after exposure to ischemia, Vcam1-deficient cardiomyocytes (both in vivo and in vitro) manifested marked attenuation of essential pro-survival cues. These include a decrease in the cardiomyocyte-leukocyte interaction-mediated induction of Ezrin and its downstream Akt and ERK1/2 phosphorylation, as well as decreased expression of tumor necrosis factor α (TNFα) and manganese superoxide dismutase 2 (Sod2) genes. Collectively, our findings uncover a VCAM-1/Ezrin axis as an essential and previously unrecognized protective mediator of cardiomyocyte homeostasis in ischemic myocardium.</p>

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VCAM-1/Ezrin axis antagonizes myocardial damage in ischemia-reperfusion injury

  • 期刊论文

  • 发表日期：

    2025年11月28日

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  • Anwarul Ferdous,
  • Ariel Diaz,
  • Daniel Daou,
  • Diana Dad Zada,
  • Nan Jiang,
  • Herman I. May,
  • Juan A. Daniel-Olivas,
  • Jan-Bernd Funcke,
  • Mayarling F. Troncoso,
  • Jafet Ortiz-Quintero,
  • Magda C. Diaz-Vesga,
  • Lorena Garcia,
  • Mario Chiong,
  • Dian J. Cao,
  • Thomas G. Gillette,
  • Sergio Lavandero,
  • Joseph A. Hill

摘要

Vascular cell adhesion molecule 1 (VCAM-1), a known downstream target of the Forkhead box O (FoxO) family of transcription factors, has well-established roles in development, cell-cell interactions, and cell survival. However, the specific role and mechanisms whereby VCAM-1 governs cardiomyocyte homeostasis in ischemic heart disease are incompletely understood. Here, we report that ischemia/reperfusion (I/R)-induced myocardial damage resulted in marked attenuation of FoxO1 and Vcam1 mRNA levels in wild-type (WT) mice, suggesting a protective role of the FoxO1/VCAM-1 axis in I/R injury. Indeed, compared with WT littermates, cardiomyocyte-specific loss of Vcam1 significantly exacerbated I/R-induced myocardial damage, apoptotic cardiomyocyte death, contractile dysfunction, and maladaptive cardiac remodeling. We go on to show that after exposure to ischemia, Vcam1-deficient cardiomyocytes (both in vivo and in vitro) manifested marked attenuation of essential pro-survival cues. These include a decrease in the cardiomyocyte-leukocyte interaction-mediated induction of Ezrin and its downstream Akt and ERK1/2 phosphorylation, as well as decreased expression of tumor necrosis factor α (TNFα) and manganese superoxide dismutase 2 (Sod2) genes. Collectively, our findings uncover a VCAM-1/Ezrin axis as an essential and previously unrecognized protective mediator of cardiomyocyte homeostasis in ischemic myocardium.