Translational research : the journal of laboratory and clinical medicine
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Recently, the CANTOS (Canakinumab Anti-Inflammatory Thrombosis Outcomes Study) showed the successful anti-inflammatory benefit of canakinumab, a monoclonal antibody targeting interleukin-1ß (IL-1ß) toward major cardiovascular events (MACE) in patients with a previous myocardial infarction (MI). The magnitude of reduction in MACE was directly attributed to a reduction witnessed in IL-6 and C-reactive protein (CRP) and highlighted the therapeutic potential of selectively targeting IL-1ß for atherosclerotic disease, a notion previously introduced in animal models. IL-1ß is involved in the downstream activation of the IL-6 receptor, which itself has been previously implicated as a target for atherothrombosis from Mendelian randomization studies. ⋯ With further discussion of the existing knowledge on the proinflammatory relationship of the NLRP3 inflammasome with atherosclerosis, this review summarizes and critically evaluates the preclinical and interventional findings of endogenous NLRP3 inflammasome inhibition in attempts to elucidate anti-inflammatory mechanisms, and therapeutic targets against atherothrombosis. Further investigation focusing on the endogenous mechanisms of inhibition of the NLRP3 inflammasome would uncover diagnostic routes from defective means in inflammatory resolution. Specifically, pro-resolving lipid mediators, autophagy, and phosphorylation/dephosphorylation mechanisms are 3 points of worthy investigation from existing evidence.
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During acute myocardial infarction (AMI), Ischemia/Reperfusion (I/R) injury causes cardiomyocyte (CM) death and loss of tissue function, making AMI one of the major causes of death worldwide. Cell-based in vitro models of I/R injury have been increasingly used as a complementary approach to preclinical research. However, most approaches use murine cells in 2D culture setups, which are not able to recapitulate human cellular physiology, as well as nutrient and gas gradients occurring in the myocardium. ⋯ Conditioned medium was further used to probe human cardiac progenitor cells (hCPCs) response to paracrine cues from injured hiPSC-CMs through quantitative whole proteome analysis (SWATH-MS). I/R injury hiPSC-CM conditioned media incubation caused upregulation of hCPC proteins associated with migration, proliferation, paracrine signaling, and stress response-related pathways, when compared to the control media incubation. Our results indicate that the model developed herein can serve as a novel tool to interrogate mechanisms of action of human cardiac populations upon AMI.