The study of the molecular mechanisms altered in the early stages after a heart attack is key to discover new therapeutic strategies aimed at reducing injuries. This has been the objective of the research carried out by investigators of the Spanish Consortium CIBER of Cardiovascular Diseases (CIBERCV) just appeared in EBioMedicine (published by The Lancet). This article postulate new therapeutic targets related to endogenous cardioprotective mechanisms to prevent myocardial damage caused during the restoration of blood flow after heart ischemia.
The collaborative study, involving the CIBERCV research groups led by Federico Mayor and Petronila Penela (Centro de Biología Molecular "Severo Ochoa" – Universidad Autónoma de Madrid, IIS La Princesa) and David García-Dorado and Javier Inserte (Cardiovascular Diseases Research Group of the Vall d'Hebron Institut de Recerca), has revealed previously unnoticed changes in the levels of two cardiac regulatory proteins (GRK2 and AKT) during the early stages of myocardial ischemia-reperfusion, which contribute to the reduction of cardioprotective capacity.
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Research group from CIBERCV at the VHIR |
Reperfusion injury
Acute myocardial infarction, due to reduced blood flow to the heart (ischemia), is a major cause of death and disability. Prompt restoration of the circulation is key to reduce mortality after this event, so current treatment protocols are mainly based on performing coronary interventions aimed at widening stenosis or occlusions in the coronary arteries (coronary angioplasty), or on delivering thrombolytic drugs . However, despite the advances that allow rapid and effective reperfusion, these clinical procedures can themselves trigger myocardial damage (reperfusion injury), which leads to a higher prevalence of arrhythmias and heart failure in patients who have survived a heart attack.
Improve cardioprotective capacity
“There are currently no effective therapies to avoid reperfusion injury, although therapeutic strategies have been postulated to boost the activation of signaling cascades, such as the AKT kinase pathway, which appear to play a cardioprotective role, and thus partially relieve ischemia-reperfusion injury”, explains Petronila Penela, first author of the study.
The researchers have found, in in isolated rat hearts and porcine preclinical models, that the levels of GRK2 and AKT proteins, very relevant in cardiovascular pathophysiology, experience a transient decrease by the action of proteases in the early stages after the ischemia-early reperfusion. "These changes deteriorate the overall protective capacity of the AKT pathway to counteract cardiac injury, thus contributing to increased reperfusion damage”, says Dr. Penela.
"Our results help to better understand the dynamic regulation of GRK2 and AKT proteins during infarction and could help explain the weakening of cardioprotective pathways during early ischemia-reperfusion”.
New therapeutic strategy
These findings open the way to new therapeutic strategies aimed at reducing reperfusion injury, based on enhancing endogenous cardioprotection mechanisms: "The prevention of transient degradation of these proteins during early reperfusion could strengthen cardiac protection therapeutic strategies in the acute myocardial infarction”, highlight the authors.
“Degradation of GRK2 and AKT is an early and detrimental event in myocardial ischemia/reperfusion” Penela P, Inserte J, Ramos P, Rodriguez-Sinovas A, Garcia-Dorado D, Mayor Jr, F. 2019, EBioMedicine. https://doi.org/10.1016/j.ebiom.2019.09.019
