Central miR-410-3p expression sex-dependently attenuates cardiometabolic dysfunction

Autonomic regulation plays a critical role in cardiovascular and metabolic homeostasis, and its disruption is associated with hypertension and cardiometabolic dysfunction. MiRNAs are small, non-coding RNAs that have emerged as powerful regulators of autonomic pathways, modulating angiotensin (Ang) II signaling, sympathetic outflow, and metabolic and hormone responses. We previously demonstrated via luciferase assays that miR-410-3p directly downregulates AGTR1, the gene that encodes the pro-hypertensive angiotensin II type 1 receptor (AT1R). In addition, we showed that central miR-410-3p overexpression attenuates acute Ang-II-induced increases in systolic blood pressure in regular diet-fed male and female mice, potentially via downregulation of AT1R signaling. However, the functional role of miR-410-3p in blood pressure and metabolic regulation during chronic cardiometabolic stress remains unclear. Notably, we found a significant reduction in hypothalamic miR-410-3p transcript levels via droplet digital PCR (ddPCR) in male (p< 0.05, n=4-5) and female (p=0.01, n=4-6) mice with high-fat diet-induced cardiometabolic disease (CMD), including Ang-II-induced hypertension, compared to regular-diet, sex-matched controls. This finding suggests a link between chronic cardiometabolic stress and central miR-410-3p downregulation, a change that may promote a more disease-permissive environment. Accordingly, in the present study, we tested the hypothesis that central overexpression of miR-410-3p will downregulate AT1R expression in brain regions governing autonomic function, resulting in the attenuation of Ang-II-driven hypertension and cardiometabolic dysfunction. Male and female C57BL/6J mice with high-fat diet-induced CMD received an intracerebroventricular (ICV) injection (2 nmol) of miR-410-3p agomiR or scramble control miRNA followed by Ang-II infusion via osmotic minipumps (450 ng/kg/min, IP, 4 weeks). Ang-II significantly increased active phase mean arterial pressure (MAP; radiotelemetry) at day 14 of infusion in scramble females, whereas this response was attenuated in miR-410-3p females (105 ± 4 vs. 123 ± 5 mmHg, n=4-5, p< 0.05). Consistent with this finding, ΔMAP from baseline to day 14 of Ang-II infusion decreased in miR-410-3p females but increased in scramble females (p< 0.01, n=4-5). Interestingly, we did not observe differences in MAP between miR-410-3p and scramble males in response to Ang-II, indicating a sex-specific effect of miR-410-3p. Furthermore, to evaluate the role of miR-410-3p in metabolic function, a glucose tolerance test (GTT) was performed before and after miRNA treatment. While there were no significant differences in glucose tolerance in males, miR-410-3p females showed improved glucose tolerance compared to their scramble counterparts (area under the curve, AUC: 31,389 ± 4,334 vs. 44,706 ± 5,110, p=0.08). Together, our findings provide novel evidence that cardiometabolic stress is associated with a downregulation of central miR-410-3p levels and that overexpression can sex-dependently attenuate Ang-II-driven hypertension and cardiometabolic dysfunction, supporting a potential therapeutic role of miR-410-3p. This study was supported by the National Institutes of Health (HL163588). This abstract was presented at the American Physiology Summit 2026 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.