Mechanistic insights into homocysteine-induced coronary microcirculatory dysfunction post-MI: The pivotal role of LncMEG3/miR-223/NLRP3 signaling axis.
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Abstract
Background: Hyperhomocysteinemia (HHcy) is known to exacerbate coronary microvascular dysfunction in patients experiencing acute myocardial infarction (AMI). However, the precise mechanisms underlying the exacerbation of injury by HHcy remain to be fully elucidated.
Methods: HHcy models were established in C57/BL6 mice and human coronary artery endothelial cells (HCAECs). Transcriptome sequencing identified differentially expressed non-coding RNAs (ncRNAs) and proteins in myocardial infarction (MI) mice with HHcy. Cardiac function and tissue morphology were assessed using small animal ultrasound imaging and hematoxylin-eosin (H&E) staining. CD31 immunofluorescence staining and ink staining were employed to evaluate microvascular density and microcirculatory function. The scratch wound healing assay was utilized to determine endothelial cell migration capacity. Quantitative real-time PCR and Western blot analysis was performed to investigate the impact of HHcy on the long non-coding RNAs (lncRNA) MEG3/microRNA-223/NLRP3 signaling pathway in vivo and in vitro.
Results: Both in vivo and in vitro studies demonstrated that HHcy could exacerbate cardiac and endothelial cell injury following MI or hypoxia through the lncRNA MEG3/microRNA-223/NLRP3 signaling pathway. HHcy suppressed miR-223 expression by upregulating lncRNA MEG3 levels, which subsequently increased NLRP3 expression and aggravated cell pyroptosis. Microcirculatory disorders arising from impaired coronary microvascular function significantly contributed to the decline in cardiac function. Targeting lncRNA MEG3 silencing or NLRP3 inhibition could attenuate the exacerbation of cardiac damage and microcirculatory dysfunction induced by HHcy after myocardial infarction.
Conclusion: HHcy exacerbates cardiac injury and microcirculatory dysfunction post-myocardial infarction through the lncRNA MEG3/microRNA-223/NLRP3 signaling pathway.
期刊介绍：
Cellular Signalling publishes original research describing fundamental and clinical findings on the mechanisms, actions and structural components of cellular signalling systems in vitro and in vivo.
Cellular Signalling aims at full length research papers defining signalling systems ranging from microorganisms to cells, tissues and higher organisms.
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