Deletion of miR-92 and its cluster promotes metabolic and arterial dysfunction, and atherosclerosis

Atherosclerosis, the leading cause of death in the US, is a chronic inflammatory disorder that is associated with arterial dysfunction and hyperlipidemia. Dysfunction of the endothelium, a single layer of cells lining the inside of arteries, is a primary risk factor for atherosclerosis. Endothelial dysfunction is characterized by altered cell metabolism and impaired vasodilation. MicroRNAs (miRs) are small non-coding RNAs that are key regulators of metabolic and cardiovascular diseases. miR-92 has also been shown to be a modulator of endothelial function. We hypothesized that deleting miR-92 would alter endothelial cell metabolism, cause vascular dysfunction, and worsen atherosclerosis. We utilized male and female whole-body miR-92 knockout (miR-92 KO) mice. Hyperlipidemia was induced by administering a single dose of Pcsk9 containing adeno-associated virus, after which mice were fed an atherogenic diet for 16 weeks until aortas were collected to assess atherosclerotic plaque burden. We assessed measures of mitochondrial metabolism in isolated primary endothelial cells (ECs), arterial function, and aortic plaque burden. Using Seahorse technology, we found that primary ECs from miR-92 knockout mice demonstrated a 25% higher rate of oxygen consumption (p<0.02), 25% higher spare respiration (p<0.02), and 61% higher proton leak (p<0.01) compared with wild-type (WT) ECs, indicating increased oxidative phosphorylation. Endothelial-dependent dilation was lower in miR-92 KO mice response to acetylcholine (Ach, 10- 9 to 10- 4 M) (maximal dilation: 72.2% vs. 38.6%, p<0.001) compared with WT mice, indicative of endothelial dysfunction. miR-92 deletion also increased pulse wave velocity (272.6 vs. 297.2 cm/s, p<0.02), a measure of large artery stiffness. Percent plaque area in the aorta was higher in miR92-deficient mice compared to WT mice (1.0 vs. 2.78%, p<0.03). In conclusion, these findings suggest that deletion of miR-92 and its cluster results in a shift towards oxidative phosphorylation in the endothelium, and this is associated with impaired vascular function and a small, but significant, increase in atherosclerotic plaque development. Together, these results suggest that miR-92 may be a potential therapeutic target to improve arterial dysfunction and reduce atherosclerosis. National Institute on Aging (R01 AG048366 and R01 AG060395) and US Department of Veterans Affairs (I01 BX004492) This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.