Wnt5a is a potent signaling molecule in the non-canonical Wnt pathway that is strongly implicated in obesity, metabolic disorders, and atherosclerosis. Secreted frizzled-related protein 5 (Sfrp5), an endogenous inhibitor of Wnt5a is an anti-inflammatory adipokine that exerts beneficial effects against metabolic dysfunction. However, little is known about the role of Sfrp5 in the pathogenesis of atherosclerosis, with contradicting results between the human and animal studies. Therefore, we aimed to investigate whether administering Sfrp5 would restore the Wnt5a-induced endothelial dysfunction in the human endothelial cells and isolated rat aorta. In addition, we sought to determine the association of serum Sfrp5 concentrations with atherosclerosis by measuring brachial-ankle pulse wave velocity (baPWV) in humans.
Transcript levels of JNK, Akt, endothelial nitric oxide synthase (eNOS) were analyzed on human umbilical vein endothelial cells (HUVECs) treated with Wnt5a in the presence or absence of Sfrp5. Isometric force displacement transducer was used for ex-vivo measurement of endothelium-dependent vasorelaxation. Circulating Sfrp5 and Wnt5a levels and baPWV were measured in 282 human subjects with type 2 diabetes.
Sfrp5 dose-dependently restored the Wnt5a-induced impaired vasorelaxation in rat thoracic aorta by an eNOS-dependent mechanism. Similarly, Sfrp5 treatment restored the Wnt5a-induced reduction of NO production via eNOS in HUVECs. The Wnt5a-induced changes in the phosphorylation of JNK, Akt, and eNOS were ameliorated with the Sfrp5 administration. In humans with type 2 diabetes, the serum Sfrp5 levels were positively correlated with their baPWV (r=0.146, p=0.024). Multivariate linear regression analysis demonstrated that serum Sfrp5 level was independently associated with baPWV after adjustment for potential confounders [B (SE)=7.40 (3.35); p=0.028].
Experimental Sfrp5 administration demonstrated an amelioration of Wnt5a-induced endothelial dysfunction via an eNOS-dependent mechanism. With the positive correlation between serum Sfrp5 concentration and arterial stiffness in diabetic patients, our findings suggest the possible compensatory action of Sfrp5 against atherosclerosis in a metabolically dysfunctional condition.