Ethyl pyruvate attenuates isoproterenol-induced myocardial infarction in rats: Insight to TNF-α-mediated apoptotic and necroptotic signaling interplay

• Published in: International immunopharmacology 2022-02, Vol.103, p.108495-108495, Article 108495
• Main Authors: Al-Botaty, Basant M., Elkhoely, Abeer, K. El-Sayed, Elsayed, Ahmed, Amany A.E.
• Format: Article
• Language: English
• Subjects: Animals; Antioxidants; Apoptosis; c-FLIP protein; Calcium-binding protein; Caspase-3; Caspase-8; Creatine; Creatine kinase; Ethyl pyruvate; Heart; Heart attacks; Heat shock proteins; Hemodynamics; Hsp70 protein; Inflammation; Interleukin 6; Isoproterenol; Kinases; Malondialdehyde; MAP kinase; Markers; Mitigation; Monocyte chemoattractant protein; Monocyte chemoattractant protein 1; Monocytes; Myocardial infarction; Myocardial Infarction - chemically induced; Myocardial Infarction - drug therapy; Myocardial Infarction - metabolism; Myocardium - pathology; Necroptosis; NF-κB protein; Nitric oxide; Nitric-oxide synthase; Oxidative Stress; Protein kinase; Protein-serine/threonine kinase; Proteins; Pyruvates - pharmacology; Pyruvates - therapeutic use; Rats; Signaling; Tumor Necrosis Factor-alpha - metabolism; Tumor necrosis factor-TNF
• ISSN: 1567-5769; 1878-1705
• DOI: 10.1016/j.intimp.2021.108495

Effect of ethyl pyruvate on tumor necrosis factor receptor pathway of apoptosis and necroptosis. Complex 1: RIPK1 ubiquitinated and deactivated by cIAPs to promote cell survival and inflammation. Under stress conditions, cIAPs are inhibited allowing RIPK1 to be deubiquitinated and autophosphorylated. Immediately RIPK1 phosphorylate RIPK3 and both form Complex 2. Two possible types of cell death could occur; either caspase 8 become activated and cleave RIPK1/RIPK3 to form complex 2a and induce apoptosis, or excessive ROS stimulate upregulation of cFLIP which in turn inhibit caspase 8 and enhance formation of necrosome complex (complex 2b). In the latter complex MLKL is recruited to be phosphorylated then bound to intracellular HSP 70 and undergoes polymerization after which it transfer to plasma membrane and disrupt its integrity to end cell life by necroptosis releasing cellular debris including HSP 70. ISO, isoproterenol; EP, ethyl pyruvate; ROS, reactive oxygen species; TNF-α, tumor necrosis factor alpha; TNR1, tumor necrosis factor receptor 1; TRADD, TNF receptor-associated death domain; TRAF2/5, TNF receptor associated factor 2 and 5; cIAPs, Cellular inhibitors of apoptosisproteins; RIPK1/3, receptor-interacting serine/threonine protein kinase 1/3; NEMO, NF-kappa-B essential modulator; IKK α/β, inhibitor of nuclear factor kappa-B kinase subunit alpha/beta; NF-κB p65, nuclear factor kappa-B subunit p65; IL-6, interleukin 6; i-NOS, inducible nitric oxide synthase; MCP-1, monocyte chemoattractant protein 1; FADD, Fas-associated protein via death domain; cFLIP, cellular FLICE-like inhibitory protein; MLKL, mixed lineage kinase domain-like protein; HSP 70, heat shock protein 70. [Display omitted] •Ethyl pyruvate ameliorates Isoproterenol-induced Myocardial infarction in rats.•Ethyl pyruvate manifests anti-inflammatory action through decreasing TNF-α- dependent NF-κB p65 pathway.•Ethyl pyruvate exerts antiapoptotic action via downregulation of TNF-α-dependent apoptotic factors; caspase 8/ cleaved caspase 3 and apoptotic regulator; cFLIP.•Ethyl pyruvate interestingly manifests antinecroptotic action via downregulation of TNF-α- dependent necroptotic factors; p-RIPK1/p-RIPK3/p-MLKL/HSP 70 signalling pathways. The current study investigated the prophylactic effect of ethyl pyruvate (EP) in Isoproterenol (ISO) - induced myocardial infarction (MI). Ethyl pyruvate (EP) was given at a dose of 100 mg/kg i.p for 7 days, while isoproterenol (ISO) was administered at a