title: Necroptotic cell death in failing heart: relevance and proposed mechanisms.
abstract: As cardiomyocytes have a limited capability for proliferation, renewal, and repair, the loss of heart cells followed by replacement with fibrous tissue is considered to result in the development of ventricular dysfunction and progression to heart failure (HF). The loss of cardiac myocytes in HF has been traditionally believed to occur mainly due to programmed apoptosis or unregulated necrosis. While extensive research work is being carried out to define the exact significance and contribution of both these cell death modalities in the development of HF, recent knowledge has indicated the existence and importance of a different form of cell death called necroptosis in the failing heart. This new cell damaging process, resembling some of the morphological features of passive necrosis as well as maladaptive autophagy, is a programmed process and is orchestrated by a complex set of proteins involving receptor-interacting protein kinase 1 and 3 (RIP1, RIP3) and mixed lineage kinase domain-like protein (MLKL). Activation of the RIP1-RIP3-MLKL signaling pathway leads to disruption of cation homeostasis, plasma membrane rupture, and finally cell death. It seems likely that inhibition of any site in this pathway may prove as an effective pharmacological intervention for preventing the necroptotic cell death in the failing heart. This review is intended to describe general aspects of the signaling pathway associated with necroptosis, to describe its relationship with cardiac dysfunction in some models of cardiac injury and discuss its potential relevance in various types of HF with respect to the underlying pathologic mechanisms.
authors.affiliation: Department of Pharmacology and Toxicology, Faculty of Pharmacy, Comenius University in Bratislava, Odbojarov 10, 832 32, Bratislava, Slovak Republic. adameova@fpharm.uniba.sk.
authors.forename: Adriana
authors.initials: A
authors.lastname: Adameova
authors.affiliation: Department of Heart Failure and Transplantation, The National Institute of Cardiovascular Diseases, Bratislava, Slovak Republic.
authors.forename: Eva
authors.initials: E
authors.lastname: Goncalvesova
authors.affiliation: Department of Pharmacology and Toxicology, Faculty of Pharmacy, Comenius University in Bratislava, Odbojarov 10, 832 32, Bratislava, Slovak Republic.
authors.forename: Adrian
authors.initials: A
authors.lastname: Szobi
authors.affiliation: Institute of Cardiovascular Sciences, St. Boniface Hospital Albrechtsen Research Centre, Winnipeg, Canada.|Department of Physiology and Pathophysiology, Faculty of Health Sciences, University of Manitoba, Winnipeg, Canada.
authors.forename: Naranjan S
authors.initials: NS
authors.lastname: Dhalla
mesh_terms: D017209:Apoptosis; D006333:Heart Failure / Q000503:physiopathology*; D006706:Homeostasis; D006801:Humans; D032383:Myocytes, Cardiac / Q000473:pathology*; D009336:Necrosis; D011494:Protein Kinases / Q000378:metabolism; D053422:Receptor-Interacting Protein Serine-Threonine Kinases / Q000378:metabolism; D015398:Signal Transduction
chemical_list: C570693:MLKL protein, human; D011494:Protein Kinases; C506249:RIPK1 protein, human; C119705:RIPK3 protein, human; D053422:Receptor-Interacting Protein Serine-Threonine Kinases
keywords: Apoptosis; Cell death; Heart failure; Maladaptive autophagy; Necroptosis; Passive necrosis