Transcriptomic Profile Of Macrophage-mediated Energy Metabolism In Sporadic Aortic Aneurysms And Acute Dissections

Background: Inflammation plays a critical role in the development of ascending thoracic aortic aneurysms (ATAA) and their progression to acute dissection (ATAD). Macrophage (MΦ) activation is associated with changes in energy metabolism. To better understand the dynamic changes of MΦ function during ATAA and ATAD development, we examined transcriptomic profiles of energy metabolism in MΦs in human aortic tissue. We hypothesized that metabolic activity in MΦs is higher in ATAA and ATAD tissues compared to non-diseased controls. Methods: We performed single-cell RNA sequencing analysis of ascending aortic tissue from 9 patients with ATAA without dissection, 9 patients with ATAD (dissected and non-dissected areas collected separately), and 8 non-diseased organ donor control subjects (Fig. 1A). Within MΦ cluster (Fig. 1B), we compared differentially expressed metabolic genes as well as metabolic flux and metabolite accumulation using single-cell flux estimation analysis between control, ATAA, and ATAD groups. Results: Compared to controls, MΦs in ATAA and ATAD exhibited increased glycolytic gene expression and glycolytic activity as well as increased anaerobic respiration and lactate accumulation (Figs. 1C, 1D). We also observed upregulated fatty acid oxidation-related genes and increased fatty acid oxidation flux in ATAD compared to control, which corresponded to lower predicted metabolite levels of fatty acid in ATAD (Figs. 1C, 1D). Furthermore, tricarboxylic acid (TCA) cycle-related genes in MΦs were higher in ATAD than in control (Fig. 1C). Interestingly, mitochondria-encoded oxidative phosphorylation (OXPHOS) genes were downregulated in MΦs of ATAD while nuclear-encoded OXPHOS genes were upregulated in MΦs of ATAD compared to controls (Fig. 1C). Conclusion: Both aerobic and anaerobic metabolic pathways exhibited higher activity in dissection, suggesting overall energy metabolism is increased to meet the energy demands of MΦs in dissection.