Targeting necroptosis as therapeutic potential in chronic myocardial infarction

Abstract

Cardiovascular diseases (CVDs) are considered the predominant cause of morbidity and mortality globally. Of these, myocardial infarction (MI) is the most common cause of CVD mortality. MI is a life-threatening condition which occurs when coronary perfusion is interrupted leading to cardiomyocyte death. Subsequent to MI, consequences include adverse cardiac remodeling and cardiac dysfunction mainly contribute to the development of heart failure (HF). It has been shown that loss of functional cardiomyocytes in MI-induced HF are associated with several cell death pathways, in particular necroptosis. Although the entire mechanism underlying necroptosis in MI progression is still not widely recognized, some recent studies have reported beneficial effects of necroptosis inhibitors on cell viability and cardiac function in chronic MI models. Therefore, extensive investigation into the necroptosis signaling pathway is indicated for further study. This article comprehensively reviews the context of the underlying mechanisms of necroptosis in chronic MI-induced HF in in vitro, in vivo and clinical studies. These findings could inform ways of developing novel therapeutic strategies to improve the clinical outcomes in MI patients from this point forward.

Keywords: Cell death pathways; Chronic myocardial infarction; Heart failure; Necroptosis.

Fig. 1

The chronological change of MI progression. The progression of MI following myocardial ischemia involves three phases. The inflammatory phase occurs 1 to 4 days after the myocardium becomes ischemic. The proliferative phase then follows and lasts for 3 to 4 weeks after MI. Lastly, the myocardium become repaired and remodeled in the healing phase at 2 to 6 weeks of MI progression. Different cell death mechanisms occur throughout the disease progression. Cardiomyocyte apoptosis could be demonstrated at as early as 2 h following MI and remains detectable up to 12 weeks. The autophagy machinery is upregulated within 1 to 3 days after MI in the rat models. At 1 week following MI, the autophagic flux becomes impaired and necroptosis emerges. Cardiomyocyte necroptosis is persistently increased up to 12 weeks in an experimental model. The progressive death of cardiomyocyte is responsible for deterioration of cardiac contractile function

Fig. 2

Regulatory mechanism of necroptosis. Under ischemic conditions, TNF-α activated TNFR1 then triggered the assembly of complex I. The activation of caspase-8 would result in cardiomyocyte loss through apoptosis pathway while, the inactivation of caspase-8 in complex Iib induced the phosphorylation of RIPK1 and RIPK3 and formed pro-necrotic complexes or necrosomes. Then, the activated p-RIPK3 would phosphorylate MLKL to p-MLKL which will be translocated from cytoplasm to the plasma membrane and mediate membrane breakdown, leading to necroptotic cell death. Under prolongation of ischemic insult, the impairment of the autophagic machinery leads to accumulation of p62 which causes necroptosis dependent cell death. In addition, the intervention with several cell death modulators could improve cardiomyocyte viability under ischemic conditions. Pan-Caspase inhibitor Z-VAD acts as an effective caspase inhibitor resulting in prevention of apoptosis. Necroptosis is inhibited by Nec-1 which inhibits the activity of RIPK1 while Alliin prevents necroptosis cell death by mitigating necroptosis markers. TNF-α: tumor necrosis factor-α; TNFR1: tumor necrosis factor receptor 1; RIPK1: receptor-interacting serine/threonine-protein kinase 1; RIPK3: receptor-interacting serine/threonine-protein kinase 3; MLKL: mixed lineage kinase domain-like; p-MLKL: phosphorylated-mixed lineage kinase domain-like; Traf2: tumor necrosis factor receptor associated factor 2; cIAP1/2: cellular inhibitors of apoptosis 1 and 2; LUBAC: linear ubiquitin chain assembly complex; CYLD: the tumor-suppressor cylindromatosis; TRADD: TNFR1-associated death domain protein; FADD: fas-associated protein with death domain; Nec-1: necrostatin 1; zVAD: pan-Caspase inhibitor carbobenzoxy-valyl-alanyl-aspartyl-[O-methyl]-fluoromethylketone; LC3-II: lipid modified form of microtubule-associated protein 1A/1B-light chain 3; p62: ubiquitin-binding protein p62