MicroRNA-126-3p Inhibits Angiogenic Function of Human Lung Microvascular Endothelial Cells via LAT1 (L-Type Amino Acid Transporter 1)-Mediated mTOR (Mammalian Target of Rapamycin) Signaling

Abstract

Objective: MicroRNA-126-3p (miR-126) is required for angiogenesis during organismal development or the repair of injured arterial vasculature. The role of miR-126 in lung microvascular endothelial cells, which are essential for gas exchange and for lung injury repair and regeneration, remains poorly understood. Considering the significant heterogeneity of endothelial cells from different vascular beds, we aimed to determine the role of miR-126 in regulating lung microvascular endothelial cell function and to elucidate its downstream signaling pathways. Approach and Results: Overexpression and knockdown of miR-126 in primary human lung microvascular endothelial cells (HLMVEC) were achieved via transfections of miR-126 mimics and antisense inhibitors. Increasing miR-126 levels in HLMVEC reduced cell proliferation, weakened tube formation, and increased cell apoptosis, whereas decreased miR-126 levels stimulated cell proliferation and tube formation. Whole-genome RNA sequencing revealed that miR-126 was associated with an antiangiogenic and proapoptotic transcriptomic profile. Using validation assays and knockdown approaches, we identified that the effect of miR-126 on HLMVEC angiogenesis was mediated by the LAT1 (L-type amino acid transporter 1), via regulation of mTOR (mammalian target of rapamycin) signaling. Furthermore, downregulation of miR-126 in HLMVEC inhibited cell apoptosis and improved endothelial tube formation during exposure to environmental insults such as cigarette smoke. Conclusions: miR-126 inhibits HLMVEC angiogenic function by targeting the LAT1-mTOR signaling axis, suggesting that miR-126 inhibition may be useful for conditions associated with microvascular loss, whereas miR-126 augmentation may help control unwanted microvascular angiogenesis.

"Regulatory Roles for miR-126 in Inflammatory Response and Programmed Death of Cardiac Myocytes Driven by Acidosis During Simulated Ischemia"

“…As shown in (Figure 4a,4b), Bcl-2 levels decreased markedly in cardiac myocytes subjected to hypoxia/ acidosis or aerobic acidosis, and the effects were blocked by KD of miR-126 in parallel with reduced apoptosis. The results suggest negative regulation of anti-apoptotic Bcl-2 by miR-126 in this model that is consistent with some previous results [41,43,44]. We quantified the expression levels of p38-MAPK and JNK in hypoxic/acidotic and aerobic-acidotic cardiac myocytes in the presence and absence of miR-126 KD.…”

Biphasic Effect of Pirfenidone on Angiogenesis

“…Endothelial cell apoptosis plays an important role in vascular degeneration and vascular remodeling during angiogenesis, which is closely related to the process of the aortic arch, lens vascular membrane development, and wound healing, and can also disrupt the formation of the vascular network and inhibit tumor progression ( Affara et al, 2007 ; Ehling et al, 2020 ; Sun et al, 2020 ). Studies have shown that promoting endothelial cell apoptosis can inhibit angiogenesis, which is beneficial in the treatment of diseases related to microvascular proliferation ( Cao et al, 2020 ). Activated caspase 9 and caspase 3 are key downstream proteins in the apoptotic protein cascade and are the main indicators of apoptosis ( Kang et al, 2019 ).…”

<p>Physiological and Pathophysiological Roles of Ion Transporter-Mediated Metabolism in the Thyroid Gland and in Thyroid Cancer</p>

“…153 Furthermore, studies have confirmed that LAT1 is the target of microRNA-126. 158,159 In summary, we can conclude that LAT1 plays an important role in the amino acid metabolism of TC. Various factors in TC caused alterations in LAT1 expression, and LAT1 transported more leucine through these changes to meet the metabolic needs of TC, thus promoting the development of TC.…”