Downregulation of microRNA-512-3p enhances the viability and suppresses the apoptosis of vascular endothelial cells, alleviates autophagy and endoplasmic reticulum stress as well as represses atherosclerotic lesions in atherosclerosis by adjusting spliced/unspliced ratio of X-box binding protein 1 (XBP-1S/XBP-1U)

Abstract

AS is an important pathological basis of cardiovascular disease. miRNAs are involved in almost all steps of AS, including the injury and dysfunction of endothelial cells and vascular smooth muscle cells. This work elucidated the biological functions of miR-512-3p in AS and probed into the underlying molecular mechanism. In the present work, ox-LDL-treated HUVECs served as the in vitro model of AS and ApoE-/- mice were nourished with a high-fat diet to establish an in vivo model of AS. Proliferation, apoptosis, and migration of HUVECs were evaluated by CCK-8, TUNEL staining, Western blot, and transwell assays. Immunofluorescence examined LC3 expression and levels of autophagy-related and ER stress-related proteins were determined by Western blot assay. In addition, starBase predicted the complementary binding sites of XBP-1 to miR-512-3p and luciferase reporter assay confirmed the interaction between miR-512-3p and XBP-1. Moreover, H&E staining was employed to evaluate atherosclerotic lesions in AS model mice. Results revealed that ox-LDL treatment decreased the proliferative and migrative activities and promoted the apoptosis of HUVECs as well as induced autophagy and ER stress, which were abrogated by miR-512-3p silencing. Importantly, ox-LDL treatment elevated miR-512-3p expression and XBP-1 was a direct target of miR-512-3p. Mechanistically, knockdown of miR-512-3p enhanced the viability, suppressed the apoptosis, and promoted the migration of ox-LDL-treated HUVECs, alleviated atherosclerotic lesions in AS model mice as well as repressed autophagy and ER stress by targeting XBP-1 to manipulate the ratio of XBP-1S/XBP-1 U.

Focus on long non-coding RNA MALAT1: Insights into acute and chronic lung diseases

“…And some therapies can impair the lncRNA-miRNA-mRNA axis to inhibit lung injury. For instance, propofol blocks the MALAT1-miR-144-GSK3β signaling axis to suppress lung IRI (Zhang J. P. et al, 2021). These results suggest a promising treatment strategy based on the lncRNA-miRNA-mRNA axis for lung injury.…”

“…Propofol impedes autophagy activation and secretion of inflammatory factors (e.g., TNF-α, IL-1β, and IL-18) via impairing the MALAT1-miR-144-GSK3β signaling axis in vitro and in vivo. Propofol eventually relieves lung IRI in mice with ischemia-reperfusion (Zhang J. P. et al, 2021).…”

“…MALAT1 abrogates miR-144 which restricts the expression of glycogen synthase kinase-3β (GSK3β). MALAT1 over-expression stimulates cell apoptosis and increases lung drying wet ratio and lung injury score in lung tissues of IRI mice (Zhang J. P. et al, 2021). Propofol impedes autophagy activation and secretion of inflammatory factors (e.g., TNF-α, IL-1β, and IL-18) via impairing the MALAT1-miR-144-GSK3β signaling axis in vitro and in vivo.…”

“…XBP-1 includes active isoform (XBP-1S) and inactive isoform (XBP-1 U). One study demonstrated that decreased ratio of XBP-1S/XBP-1U results in suppressing ERS (Ge et al, 2021). MALAT1 over-expression abates miR-135a-5p to attenuate XBP-1S and elevated XBP-1 U.…”

Autophagy, Pyroptosis, and Ferroptosis: New Regulatory Mechanisms for Atherosclerosis

“…The expression of autophagy markers ATG13 and LC3 in aortic intimal ECs with severe atherosclerosis was found to be significantly higher than the expression in those without atherosclerosis ( Chen et al, 2017 ). Severe oxidative stress or inflammation stimulates excessive autophagy, leading to autophagy-dependent cell death, decreased collagen synthesis, thinning of the fibrous cap, plaque instability, lesions thrombosis, restenosis, and acute coronary events ( Cai et al, 2018 ; Ge et al, 2021 ). Thus, the resistance to excessive autophagy in an early stage is critical in preventing arteriosclerosis, further leading to serious cardiovascular complications.…”