Polymer Conjugation of Docosahexaenoic Acid Potentiates Cardioprotective Therapy in Preclinical Models of Myocardial Ischemia/Reperfusion Injury

Autores de CIPF

• Irene Dolz Pérez

  Autor

• Delia Castellano Izquierdo

  Autor

• Nahuel Aquiles García

  Autor

• Imelda Ontoria Oviedo

  Autor

• Vicent Josep Nebot Carda

  Autor

• Hernán González-King

  Autor

• Pilar Sepulveda Sanchis

  Autor

• 

  Maria Jesus Vicent Docon

  Autor

Participantes ajenos a CIPF

• Tejedor, S
• Decker, CG
• Hernandiz, A
• Diez, JL
• Alvarez, R
• Igual, B

Grupos de Investigación

• Laboratorio de Polímeros Terapéuticos

  

  Jefe/a de Grupo

  Maria Jesus Vicent Docon

Abstract

While coronary angioplasty represents an effective treatment option following acute myocardial infarction, the reperfusion of the occluded coronary artery can prompt ischemia-reperfusion (I/R) injury that significantly impacts patient outcomes. As omega-3 polyunsaturated fatty acids (PUFAs) have proven, yet limited cardioprotective abilities, an optimized polymer-conjugation approach is reported that improves PUFAs bioavailability to enhance cardioprotection and recovery in animal models of I/R-induced injury. Poly-l-glutamic acid (PGA) conjugation improves the solubility and stability of di-docosahexaenoic acid (diDHA) under physiological conditions and protects rat neonatal ventricular myocytes from I/R injury by reducing apoptosis, attenuating autophagy, inhibiting reactive oxygen species generation, and restoring mitochondrial membrane potential. Enhanced protective abilities are associated with optimized diDHA loading and evidence is provided for the inherent cardioprotective potential of PGA itself. Pretreatment with PGA-diDHA before reperfusion in a small animal I/R model provides for cardioprotection and limits area at risk (AAR). Furthermore, the preliminary findings suggest that PGA-diDHA administration in a swine I/R model may provide cardioprotection, limit edema and decrease AAR. Overall, the evaluation of PGA-diDHA in relevant preclinical models provides evidence for the potential of polymer-conjugated PUFAs in the mitigation of I/R injury associated with coronary angioplasty.

Keywords

• cardioprotection; ischemia; reperfusion injury; polymer– drug conjugates; polymer therapeutics; polypeptides; polyunsaturated fatty acids