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Aims <p>Endothelial dysfunction and impaired angiogenesis are hallmarks of ischemic heart disease and critical determinants of adverse cardiovascular outcomes after myocardial infarction (MI). While conventional cardiovascular risk factors (CVRFs) are known contributors, the specific role of MI itself triggering endothelial dysfunction remains unclear. This study aims to assess the direct impact of MI on endothelial function, independent of cardiovascular risk factors, using human and porcine endothelial colony-forming cells (ECFCs) as a surrogate cellular model.</p> Methods and results <p>Human ECFCs (hECFCs) were isolated from the peripheral blood of healthy volunteers (Control-hECFCs, n = 6), patients immediately after MI (AMI-hECFCs, n = 6), and patients 6 months after MI (CMI-hECFCs, n = 6). To evaluate the direct effect of MI independently of CVRFs, a porcine model was used: healthy pigs (n = 6) underwent 90 min of myocardial ischemia by coronary balloon occlusion followed by reperfusion. Porcine ECFCs (pECFCs) were isolated before MI (Control-pECFCs) and one month after MI (CMI-pECFCs, n = 6). In vitro, CMI-hECFCs and CMI-pECFCs had delayed colony formation, whereas AMI-hECFCs did not. Morphological alterations were observed in AMI-hECFCs and CMI-hECFCs (area and shape), while only shape changes were found in CMI-pECFCs. Senescence was increased in AMI-hECFCs and CMI-hECFCs, but not in CMI-pECFCs. Elevated oxidative stress was only detected in CMI-hECFCs. Functional angiogenic and proliferative capacities were reduced in AMI-hECFCs, CMI-hECFCs and CMI-pECFCs; however, only CMI-hECFCs and CMI-pECFCs displayed impaired migration. Molecular analysis showed overactivation of the MSK2/MKK3/p53 signalling axis in dysfunctional ECFCs, while synergistic inhibition of the axis partially restored ECFC function.</p> Conclusions <p>MI induces sustained ECFC dysfunction independently of cardiovascular risk factors. Targeting the MSK2/MKK3/p53 pathway may be a promising therapeutic strategy to restore endothelial function and improve angiogenesis after MI.</p> Graphical abstract <p></p>

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Myocardial infarction induces endothelial dysfunction with independence of cardiovascular risk factors

  • 期刊论文

  • 发表日期：

    2025年9月30日

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  • Francisco Rafael Jimenez-Trinidad,
  • Núria Solanes,
  • Marta Arrieta,
  • Blanca Llonch,
  • Mercè Roqué,
  • Xavier Freixa,
  • Salvatore Brugaletta,
  • Luis Ortega-Paz,
  • Juan José Rodríguez,
  • Pedro Cepas-Guillen,
  • Gemma Vilhaur,
  • Manel Sabaté,
  • Ana Paula Dantas,
  • Olga Tura-Ceide,
  • Montserrat Rigol

摘要

Aims

Endothelial dysfunction and impaired angiogenesis are hallmarks of ischemic heart disease and critical determinants of adverse cardiovascular outcomes after myocardial infarction (MI). While conventional cardiovascular risk factors (CVRFs) are known contributors, the specific role of MI itself triggering endothelial dysfunction remains unclear. This study aims to assess the direct impact of MI on endothelial function, independent of cardiovascular risk factors, using human and porcine endothelial colony-forming cells (ECFCs) as a surrogate cellular model.

Methods and results

Human ECFCs (hECFCs) were isolated from the peripheral blood of healthy volunteers (Control-hECFCs, n = 6), patients immediately after MI (AMI-hECFCs, n = 6), and patients 6 months after MI (CMI-hECFCs, n = 6). To evaluate the direct effect of MI independently of CVRFs, a porcine model was used: healthy pigs (n = 6) underwent 90 min of myocardial ischemia by coronary balloon occlusion followed by reperfusion. Porcine ECFCs (pECFCs) were isolated before MI (Control-pECFCs) and one month after MI (CMI-pECFCs, n = 6). In vitro, CMI-hECFCs and CMI-pECFCs had delayed colony formation, whereas AMI-hECFCs did not. Morphological alterations were observed in AMI-hECFCs and CMI-hECFCs (area and shape), while only shape changes were found in CMI-pECFCs. Senescence was increased in AMI-hECFCs and CMI-hECFCs, but not in CMI-pECFCs. Elevated oxidative stress was only detected in CMI-hECFCs. Functional angiogenic and proliferative capacities were reduced in AMI-hECFCs, CMI-hECFCs and CMI-pECFCs; however, only CMI-hECFCs and CMI-pECFCs displayed impaired migration. Molecular analysis showed overactivation of the MSK2/MKK3/p53 signalling axis in dysfunctional ECFCs, while synergistic inhibition of the axis partially restored ECFC function.

Conclusions

MI induces sustained ECFC dysfunction independently of cardiovascular risk factors. Targeting the MSK2/MKK3/p53 pathway may be a promising therapeutic strategy to restore endothelial function and improve angiogenesis after MI.

Graphical abstract