*4.4. FGF23*/*Klotho and Atherosclerosis*

Vascular endothelial dysfunction is one of the first events in the atherosclerotic process. The endothelial injury allows monocyte adhesion with subsequent infiltration into the subintimal space. Subsequently, these monocytes are di fferentiated into macrophages, beginning an inflammatory process with the release of proinflammatory cytokines and nuclear translocation of NF-kB. This inflammatory process produces changes in vascular smooth muscle cells (VSMC) from contractile to a synthetic phenotype with a higher capability to migrate from the media to the intima layer in arteries. In this space, both macrophages and VSMC accumulate lipids resulting in the formation of an atherosclerotic plaque with a fibrous cap on the luminal side of the vessel [62].

The atherosclerotic process is also associated with Wnt signaling activation. There is a positive correlation between the severity of the atherosclerotic lesion and serum Wnt5a levels. Moreover, Wnt5a staining has been detected in intimal areas of macrophage accumulation in atherosclerotic lesions of apolipoprotein-deficient mice, and human endarterectomy samples. Christman et al. showed that oxidized LDL induced Wnt5a expression, a potential mechanism to activate Wnt signaling (Figure 2) [63]. Other authors have shown that elevated concentrations of oxidized LDL induce a decrease in renal Klotho expression [64].

Similarly, in human umbilical vein endothelial cell (HUVEC), recombinant Klotho supplementation can attenuate oxidized-LDL-induced oxidative stress through upregulating oxidative scavengers (SOD and NO) [65]. Certainly, more studies are necessary to confirm the potential interaction between oxidized LDL, Klotho, Wnt, and atherosclerosis progression.

In a recent publication, we have reported a significant association between FGF23 levels and carotid intimal media thickness. In 939 subjects with coronary heart disease without CKD enrolled in the CORDIOPREV study, we found that FGF23 was independently associated with intima-media thickness of both common carotid arteries [66].

Chen et al. observed that in hemodialysis patients, sclerostin was also positively associated with carotid intima-media thickness, and patients with low baseline serum sclerostin displayed a better survival. Interestingly, in this study, the authors found a negative association of sclerostin with sKlotho [67]. Although in these patients, low sKlotho levels are caused by the advanced state of CKD, it is unknown if low sKlotho levels also cause high levels of sclerostin. At the moment, it is unknown whether FGF23 through the Wnt signaling might promote the atherosclerotic process.
