The Role of Adiposomal miRNA Cargo in Diabetes-associated Cardiovascular Diseases

Background: Adipose tissue-derived extracellular vesicles (adiposomes) are emerging as key mediators of intercellular communication, playing a critical role in the pathogenesis of metabolic diseases, including diabetes. These vesicles carry bioactive molecules, such as microRNAs (miRNAs), that can modulate various cellular processes, including inflammation, vascular function, and metabolic regulation. Our previous studies demonstrated that adiposomes from obese diabetic individuals induce endothelial dysfunction and vascular remodeling, and impair microvascular flow-induced dilation, all of which are pivotal in the development of cardiovascular diseases. However, the adiposomal content that contributes to these effects is not known. This study explores the adiposomal miRNA profiles as a potential contributor to the higher cardiovascular risk among obese diabetic patients. Methods: adipose tissue samples were collected from obese subjects who were classified based on their fasting plasma glucose and hemoglobin A1C into three groups, non-diabetic (n=17), pre-diabetic (n=10), and diabetic (n=14). Adiposomes were isolated from the obtained adipose tissues and characterized using nanoparticle tracking and electron microscopy. miRNAs were extracted from the isolated adiposomes followed by miRNA sequencing, bioinformatic analysis, and correlation with other anthropometric and cardiometabolic risk measurements including (1) body fat and lean percent using DEXA scan, (1) glucose and lipid metabolic profiles, (3) brachial artery flow-mediated dilation, (4) flow-induced dilation in isolated arterioles, (5) systolic and diastolic function measured by echocardiography, and (5) circulating markers such as IL-6, CRP, and nitric oxide (NO). Results: Through comprehensive profiling of adiposomal miRNAs, we identified a distinct miRNA signature in the diabetic and prediabetic groups compared to the non-diabetic group. The topmost differentially expressed miRNAs included miR-361, miR-21, miR-130a, miR-181a, miR-10a, miR-126, miR-30e, miR-92b, miR-125a, and miR-221. The dysregulation of these miRNAs is known to be associated with hypertension, atherosclerosis, and hypertrophic cardiomyopathy. miRNAs such as miR-221, miR-361, and miR-21 were upregulated by 3 to 4 folds in the diabetic versus nondiabetic patients and correlated significantly with hemoglobin A1C and insulin resistance index HOMA-IR. Regression analyses revealed significant associations between these miRNAs and several cardiometabolic risk factors: BMI, fat percent, arteriolar flow-induced dilation, brachial artery flow-mediated dilation, and impaired lipid metabolism (higher LDL). In conclusion, the ability of obese diabetic adiposomes to disrupt cardiometabolic function is partly attributed to the dysregulated miRNA cargo. Mechanistic studies are in progress to decipher pathways impacted by the adiposomal-dysregulated miRNA cargo. This project was funded by the National Institute of Health grant number R01HL161386 and the University of Illinois-College of Medicine's Strategic Initiative This abstract was presented at the American Physiology Summit 2025 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.