Programmed necrosis in heart disease: Molecular mechanisms and clinical implications

Programmed cell death plays an essential role in myocardial homeostasis and pathology. Three distinct forms of programmed cell death have been identified, namely apoptosis, necrosis, and autophagic cell death. Necrosis, previously known as an unregulated form of cell death, has been recognized as a highly regulated process now and attracted great attention over the past decade. Programmed necrosis mainly refers to necroptosis, pyroptosis, ferroptosis, and mitochondrial permeability transition (MPT)-dependent necrosis. Among them, role of necroptosis and MPT-dependent necrosis in the pathogenesis of heart disease, mainly including myocardial infarction (MI), ischemia/reperfusion (I/R), and heart failure is well defined now. Necroptosis is orchestrated by a complex of proteins involving receptor-interacting protein kinase 1 (RIPK1), RIPK3 and mixed lineage kinase domain-like protein (MLKL). While MPT-dependent necrosis is another modality of necrosis characterized by MPT pore opening and cyclophilin-D (CypD)-dependent death signaling. Of note, the observed effects of necrostatin-1 (Nec-1, inhibitor of RIPK1) and cyclosporine A (CsA, inhibitor of CypD) on attenuating programmed necrosis and related cardiac injury further demonstrated the significant role of programmed necrosis in dictating cell demise and shed light on their further clinical application, along with other types of inhibitors targeting programmed necrosis. In this review, we summarized the recent progress on programmed necrosis in heart disease from molecular mechanisms to therapeutic strategies.