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Abstract
AimMyocardial infarction (MI) is a severe disease with increased mortality and disability rates, posing heavy economic burden for society. Exosomes were uncovered to mediate intercellular communication after MI. This study aims to explore the effect and mechanism of lncRNA KLF3-AS1 in exosomes secreted by human mesenchymal stem cells (hMSCs) on pyroptosis of cardiomyocytes and MI.MethodsExosomes from hMSCs were isolated and identified. Exosomes from hMSCs with transfection of KLF3-AS1 for overexpression were injected into MI rat model or incubated with hypoxia cardiomyocytes. Effect of KLF3-AS1 on MI area, cell viability, apoptosis, and pyroptosis was determined. The relationship among miR-138-5p, KLF3-AS1, and Sirt1 was verified by dual-luciferase reporter assay. Normal cardiomyocytes were transfected with miR-138-5p inhibitor or sh-Sirt1 to clarify whether alteration of miR-138-5p or sh-Sirt1 can regulate the effect of KLF3-AS1 on cardiomyocytes.ResultsExosomes from hMSCs were successfully extracted. Transfection of KLF3-AS1 exosome in rats and incubation with KLF3-AS1 exosome in hypoxia cardiomyocytes both verified that overexpression of KLF3-AS1 in exosomes leads to reduced MI area, decreased cell apoptosis and pyroptosis, and attenuated MI progression. KLF3-AS1 can sponge miR-138-5p to regulate Sirt1 expression. miR-138-5p inhibitor transfection and KLF3-AS1 exosome incubation contribute to attenuated pyroptosis and MI both in vivo and in vitro, while transfection of sh-Sirt1 could reverse the protective effect of exosomal KLF3-AS1 on hypoxia cardiomyocytes.ConclusionLncRNA KLF3-AS1 in exosomes secreted from hMSCs by acting as a ceRNA to sponge miR-138-5p can regulate Sirt1 so as to inhibit cell pyroptosis and attenuate MI progression.
Highlights
Myocardial infarction (MI) is a severe coronary arteryrelated disease, mainly resulted from disruption of coronary atherothrombosis or imbalance of myocardial oxygen supply-demand [1,2,3]
We further investigated the potential of exosomal KLF3AS1 derived from human mesenchymal stem cells (hMSCs) in attenuating cardiomyocyte pyroptosis and MI
After 3 days of incubation, hMSCs were grown into logarithmic growth phase, while after incubation for 6 and 7 days, cells were shifted into plateau phase and decline phase
Summary
Myocardial infarction (MI) is a severe coronary arteryrelated disease, mainly resulted from disruption of coronary atherothrombosis or imbalance of myocardial oxygen supply-demand [1,2,3]. The released plaque could accumulate platelet, leading to coronary artery occlusion and resulting in myocardial ischemia and necrosis [4]. Various cell death mechanisms, including apoptosis, pyroptosis, and necrocytosis, can be activated in response to myocardial ischemia when nutrients and oxygen are deprived [5]. GSDMD, an effector of pyroptosis, can be cleaved by caspase-1 which allows the releasing of N-terminal pore-forming domain to insert into the plasma membrane [9, 10]. Gasdermin D pores mediate osmotic cell swelling, rupture of the plasma membrane, and release of intracellular contents including the enzyme lactate dehydrogenase. Pyroptosis shares the same characteristics with cell apoptosis but featured with cell swelling and plasma membrane disruption [11]. The molecular mechanisms underlying pyroptosis in cardiomyocytes are still obscure
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