Atherosclerosis is the largest cause of human mortality, producing stroke and heart attack when fatty plaques obstructing arteries rupture. There is accordingly a great deal of research aimed at influencing the course of the condition. Reversal of plaque growth to clear arteries and remove potentially unstable plaques remains a challenge, and few approaches have been shown to achieve this goal with any reliability even in animal studies. Conversely, many different approaches have been shown to slow the development of atherosclerosis in high fat diet mouse models of the condition. The example here is a demonstration of the degree to which maladaptive fat tissue metabolism contributes to the environment of inflammation and cell stress that accelerates the growth of atherosclerotic plaque. Unfortunately, like so many other approaches, reducing inflammation (via many different means) has not been shown to significantly regress established plaque in and of itself.
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+ macrophage content and α-SMA+ 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.
