Inhibition of Adipocyte Na/K-ATPase Signaling Attenuates Atherosclerosis

Atherosclerosis is an inflammatory disease that is the main cause of cardiovascular disease and remains the leading cause of death worldwide. Adipocyte dysfunction is closely associated with oxidative stress and chronic inflammation, which contribute to systemic metabolic disturbances and atherosclerosis. We previously identified Na/K-ATPase (NKA) α1 as a signal transducer that activates Src kinase and promotes oxidative stress and inflammation in various cell types, including adipocytes. NaKtide, a peptide inhibitor of NKA signaling, has been shown to reduce systemic oxidative stress and inflammation in vivo. Here, we investigated the role of adipocyte-specific NKA signaling in atherosclerosis progression. Adipocyte-specific NaKtide (Adipo-NaKtide) was delivered to Apoe-/- mice using a lentiviral vector under the adiponectin promoter. The mice were then fed a Western Diet (WD) for 12 weeks to induce atherosclerosis. At the end of the diet feeding, atherosclerotic plaque burden was assessed in the aortic arch and sinus. Inflammatory and oxidative stress markers were analyzed in adipose tissue and plasma. Adipo-NaKtide reduced atherosclerotic plaque area by 67% in the aortic arch and 47% in the aortic sinus. CD68+ macrophage and α-SMA+ smooth muscle cell content in the aortic sinus was decreased by 45% and 53%, respectively. These vascular improvements were accompanied by dampened adipose tissue inflammation and oxidative stress, improved glucose tolerance, and lowered systemic inflammation. These findings highlight a critical contributing role for adipocyte NKA signaling in atherosclerosis and support the therapeutic potential of NaKtide in cardiometabolic disease. Funded by NIH 1R01 HL164460-01A1. 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.