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Review
. 2023 Jul 17;10(7):303.
doi: 10.3390/jcdd10070303.

Pharmaceutical Therapies for Necroptosis in Myocardial Ischemia-Reperfusion Injury

Yinchang Zhang  1 , Yantao Zhang  1 , Jinlong Zang  1 , Yongnan Li  1 , Xiangyang Wu  1
Affiliations
Review

Pharmaceutical Therapies for Necroptosis in Myocardial Ischemia-Reperfusion Injury

Yinchang Zhang et al. J Cardiovasc Dev Dis. .

Abstract

Cardiovascular disease morbidity/mortality are increasing due to an aging population and the rising prevalence of diabetes and obesity. Therefore, innovative cardioprotective measures are required to reduce cardiovascular disease morbidity/mortality. The role of necroptosis in myocardial ischemia-reperfusion injury (MI-RI) is beyond doubt, but the molecular mechanisms of necroptosis remain incompletely elucidated. Growing evidence suggests that MI-RI frequently results from the superposition of multiple pathways, with autophagy, ferroptosis, and CypD-mediated mitochondrial damage, and necroptosis all contributing to MI-RI. Receptor-interacting protein kinases (RIPK1 and RIPK3) as well as mixed lineage kinase domain-like pseudokinase (MLKL) activation is accompanied by the activation of other signaling pathways, such as Ca2+/calmodulin-dependent protein kinase II (CaMKII), NF-κB, and JNK-Bnip3. These pathways participate in the pathological process of MI-RI. Recent studies have shown that inhibitors of necroptosis can reduce myocardial inflammation, infarct size, and restore cardiac function. In this review, we will summarize the molecular mechanisms of necroptosis, the links between necroptosis and other pathways, and current breakthroughs in pharmaceutical therapies for necroptosis.

Keywords: MLKL; RIPK1; RIPK3; myocardial ischemia–reperfusion; necroptosis; pharmaceutical therapies.

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Conflict of interest statement

The authors declare no conflict of interest in relation to the subject of this review.

Figures

Figure 1
Figure 1
Simplified version of necroptosis signal transduction events downstream of tumor necrosis factor-α/tumor necrosis factor receptor (TNFα/TNFR) interactions. Soluble TNFα binds TNFR and can trigger the formation of a pro-apoptotic (left, complex I) or pro-necroptotic (right, complex IIb) complex. In the absence of caspase-8, the pro-necroptotic complex IIb forms. After phosphorylation of RIPK1 and RIPK3, RIPK3 phosphorylates MLKL, which subsequently oligomerizes and is thought to be inserted into the cell membrane, forming pores. After cell membrane permeabilization, cytokines and intracellular contents are relapsed into the extracellular environment. Figure created through BioRender.com.
See this image and copyright information in PMC

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Grants and funding

The study was funded by the Natural Sciences Foundation of Gansu (No. 23JRRA0972), the Natural Sciences Foundation of Fujian (No. 2022J05105), the Science and Technology Planning Project of Chengguan District (2022RCCX0023), the Cuiying Graduate Supervisor Applicant Training Program of Lanzhou University Second Hospital (No. 201709), the Cuiying Scientific and Technological Innovation Program of Lanzhou University Second Hospital (No. CY2022-MS-A03), the Talent Introduction Plan of the Lanzhou University Second Hospital (No. YJRCKYQDJ-2021-02).