Na/K-ATPase Signaling in Adipocytes Promotes Atherosclerosis

Adipocyte dysfunction is closely associated with oxidative stress and chronic inflammation, which contribute to systemic metabolic disturbances and atherosclerosis. We previously identified the NKA (Na/K-ATPase) α1 subunit as a signal transducer that activates Src-family kinases and promotes oxidative stress and inflammation in various cell types, including adipocytes and macrophages. NaKtide, a peptide inhibitor of NKA signaling, has been shown to reduce systemic oxidative stress and inflammation in vivo. In this study, we investigated the role of adipocyte-specific NKA signaling in atherosclerosis.

Adipocyte-specific NaKtide was delivered to Apoe^-/- mice using a lentiviral vector under the adiponectin promoter. The mice were then fed a Western diet for 12 weeks to induce atherosclerosis and then assessed for atherosclerotic plaque burden in the aortic arch and at the level of the aortic sinus. Inflammatory and oxidative stress markers were analyzed in adipose tissue and plasma.

Adipocyte-specific NaKtide reduced atherosclerotic plaque area by 67% in the aortic arch and by 48% in the aortic sinus. CD68+ (cluster of differentiation 68) macrophage content and α-SMA+ (α-smooth muscle actin) smooth muscle cell content in the aortic sinus were decreased by 45% and 53%, respectively. These vascular improvements were accompanied by dampened adipose tissue inflammation and oxidative stress, improved glucose tolerance, and reduced systemic inflammation.

These findings highlight a critical contributing role for adipocyte NKA signaling in atherosclerosis, suggesting an important endocrine and paracrine influence of adipose tissue on large artery atherogenesis and supporting the therapeutic potential of targeting NKA in cardiometabolic disease.