Obesity Increases Atherosclerosis Susceptibility via an Intertissue miR-30e-SLC7A11 Axis.

Abstract

With obesity as a risk factor for atherosclerotic disease, recent research suggests that adipose tissue in obese animal models and humans can generate endocrine-like molecules that affect arterial health. Previous studies showed that microRNA-30e (miR-30e) levels are elevated in atherosclerosis and solute carrier family 7 member 11 (SLC7A11), a cystine/glutamate transporter, is involved in atherogenesis. However, whether an endocrine-like link between the adipose-derived miR-30e-5p and SLC7A11 in the vascular endothelium can lead to obesity-caused atherosclerosis is unknown. miRNA data mining and reverse transcription-polymerase chain reaction validations were used to demonstrate the positive association among serum levels of miR-30e-5p, obesity, and coronary arterial disease in human patients. Transcriptomics (bulk RNA sequencing and single-nucleus RNA sequencing), metabolomics, and in silico analysis were used to establish a miR-30e-5p-SLC7A11 regulation of central carbon metabolism, mitochondrial and endothelial cell (EC) function. Mouse models with EC-specific <i>Slc7a11</i> knockout (EC-<i>Slc7a11</i>^-/-) and gain- or loss-of- function of miR-30e-5p were used to elucidate the detrimental role of this endocrine-like axis in obesity-related atherosclerosis. The level of adipocyte-derived miR-30e-5p was significantly upregulated in obese human patients with coronary artery disease and in obese and atherosclerotic mice. Mediated through serum exosomes, the adipocyte-generated miR-30e-5p targeted <i>SLC7A11</i> mRNA in vascular ECs. SLC7A11 deficiency due to miR-30e-5p targeting dysregulated glutamate/cystine metabolism, increased glycolysis, reduced oxidative phosphorylation, and impaired mitochondrial function. The EC dysfunction could be rectified by SLC7A11 overexpression or miR-30e-5p antagonism. Administration of exogenous miR-30e-5p or white adipose tissue-derived exosomes phenocopied the increased atherosclerosis in EC-<i>Slc7a11</i>^-/- mice. In contrast, miR-30e-5p antagomir or GW4869 treatment reduced atherosclerosis in <i>Apoe</i>^-/- and <i>ob/ob</i> mice. Our multiomics approaches demonstrate that the adipose-derived miR-30e-5p downregulated <i>SLC7A11</i> mRNA in ECs via tissue crosstalk. The resulting EC dysfunction led to obesity-related atherosclerosis in mice. These findings underscore a causality between obesity and atherosclerosis in the context of cardiovascular-kidney-metabolic syndrome.