title: Calcium-mediated cell death during myocardial reperfusion.
abstract: Reperfusion may induce additional cell death in patients with acute myocardial infarction receiving primary angioplasty or thrombolysis. Altered intracellular Ca(2+) handling was initially considered an essential mechanism of reperfusion-induced cardiomyocyte death. However, more recent studies have demonstrated the importance of Ca(2+)-independent mechanisms that converge on mitochondrial permeability transition (MPT) and are shared by cardiomyocytes and other cell types. This article analyses the importance of Ca(2+)-dependent cell death in light of these new observations. Altered Ca(2+) handling includes increased cytosolic Ca(2+) levels, leading to activation of calpain-mediated proteolysis and sarcoplasmic reticulum-driven oscillations; this can induce hypercontracture, but also MPT due to the privileged Ca(2+) transfer between sarcoplasmic reticulum and mitochondria through cytosolic Ca(2+) microdomains. In the opposite direction, permeability transition can worsen altered Ca(2+) handling and favour hypercontracture. Ca(2+) appears to play an important role in cell death during the initial minutes of reperfusion, particularly after brief periods of ischaemia. Developing effective and safe treatments to prevent Ca(2+)-mediated cardiomyocyte death in patients with transient ischaemia, by targeting Ca(2+) influx, intracellular Ca(2+) handling, or Ca(2+)-induced cell death effectors, is an unmet challenge with important therapeutic implications and large potential clinical impact.
authors.affiliation: Universitat Autònoma de Barcelona, Barcelona, Spain. dgdorado@vhebron.net
authors.forename: David
authors.initials: D
authors.lastname: Garcia-Dorado
authors.forename: Marisol
authors.initials: M
authors.lastname: Ruiz-Meana
authors.forename: Javier
authors.initials: J
authors.lastname: Inserte
authors.forename: Antonio
authors.initials: A
authors.lastname: Rodriguez-Sinovas
authors.forename: Hans Michael
authors.initials: HM
authors.lastname: Piper
mesh_terms: D002118:Calcium / Q000378:metabolism*; D002154:Calpain / Q000378:metabolism; D016923:Cell Death; D006801:Humans; D008929:Mitochondria, Heart / Q000378:metabolism*; D033681:Mitochondrial Membrane Transport Proteins / Q000378:metabolism; D009203:Myocardial Infarction / Q000378:metabolism* / Q000473:pathology; D015425:Myocardial Reperfusion / Q000009:adverse effects*; D015428:Myocardial Reperfusion Injury / Q000378:metabolism*; D009206:Myocardium / Q000378:metabolism* / Q000473:pathology; D032383:Myocytes, Cardiac / Q000378:metabolism*; D012519:Sarcoplasmic Reticulum / Q000378:metabolism
chemical_list: D033681:Mitochondrial Membrane Transport Proteins; D002154:Calpain; D002118:Calcium