Abstract
Extensive research work has been carried out to define the exact significance and contribution of regulated necrosis-like cell death program, such as necroptosis to cardiac ischemic injury. This cell damaging process plays a critical role in the pathomechanisms of myocardial infarction (MI) and post-infarction heart failure (HF). Accordingly, it has been documented that the modulation of key molecules of the canonical signaling pathway of necroptosis, involving receptor-interacting protein kinases (RIP1 and RIP3) as well as mixed lineage kinase domain-like pseudokinase (MLKL), elicit cardioprotective effects. This is evidenced by the reduction of the MI-induced infarct size, alleviation of myocardial dysfunction, and adverse cardiac remodeling. In addition to this molecular signaling of necroptosis, the non-canonical pathway, involving Ca2+/calmodulin-dependent protein kinase II (CaMKII)-mediated regulation of mitochondrial permeability transition pore (mPTP) opening, and phosphoglycerate mutase 5 (PGAM5)–dynamin-related protein 1 (Drp-1)-induced mitochondrial fission, has recently been linked to ischemic heart injury. Since MI and HF are characterized by an imbalance between reactive oxygen species production and degradation as well as the occurrence of necroptosis in the heart, it is likely that oxidative stress (OS) may be involved in the mechanisms of this cell death program for inducing cardiac damage. In this review, therefore, several observations from different studies are presented to support this paradigm linking cardiac OS, the canonical and non-canonical pathways of necroptosis, and ischemia-induced injury. It is concluded that a multiple therapeutic approach targeting some specific changes in OS and necroptosis may be beneficial in improving the treatment of ischemic heart disease.
Highlights
The pathogenesis of ischemic heart disease, which accounts for about 20% of all deaths in the European Union [1], is associated with cardiac cell death
While the role of apoptosis in the pathogenesis of ischemia-induced cardiac damage has not been fully established it has become evident that non-apoptotic cell death modalities manifesting with necrotic morphology, such as necroptosis, ferroptosis, and pyroptosis, are more important than apoptosis itself
These modalities can operate standalone or in the cooperation with other cell death programs and thereby serve in the development of infarct size and worsening heart function as well as cardiac remodeling due to ischemia. These phenotypes of ischemic injury have been viewed to occur as a result of oxidative stress (OS), and there is evidence indicating altered production/degradation of reactive oxygen species (ROS) during necroptosis
Summary
The pathogenesis of ischemic heart disease, which accounts for about 20% of all deaths in the European Union [1], is associated with cardiac cell death. In the context of MI and post-ischemic HF, these cell death programs produce deleterious cellular responses; it has not been clarified to which extent these contribute to the development of infarct size and what is the exact proportion of their occurrence in any particular cardiac disease. Other studies in the field of pyroptosis have indicated a role of OS in the signaling of this programmed necrosislike cell death In this regard, NADPH oxidase enzyme isoform 4 (NOX4) can be a critical source of cardiac OS in hypercholesterolemia [57], I/R injury [58], as well as in post-ischemic. An attempt will be made to analyze observations from various experimental cardiac studies dealing with this paradigm to test the hypothesis whether a modulation of OS could be a part of a cardioprotective, anti-necroptotic strategy, in a manner similar to approaches targeting the key necroptotic molecules such as RIP1, RIP3, and mixed lineage kinase domain-like pseudokinase (MLKL)
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