Expression of FGF23/KLOTHO system in human vascular tissue

Higher serum fibroblast growth factor 23 (FGF23) levels are independently associated with impaired vasoreactivity and increased arterial stiffness and, in patients with stable coronary artery disease (CAD), with cardiovascular events and mortality. Additionally, the secreted form of Klotho protein, formed by protelytic cleavage on the cell surface by ADAM-17, may also function as a humoral factor, and has been potentially related to the protective mechanism against endothelial dysfunction by upregulating the anti-inflamatory cytokine IL-10 in vascular tissue.
Therefore, emerging evidence suggests that FGF23 and KLOTHO are factors potentially related to cardiovascular morbidity and mortality, raising the question whether FGF23-KLOTHO axis is involved in vascular pathology. Since, the expression of FGF23, FGFRs and KLOTHO in human vascular tissue remains unproved we aimed to study the expression of members of the FGF23-KLOTHO axis in vascular tissue and, in addition, we also analyzed the expression of ADAM-17 and IL-10, factors related to KLOTHO functionality.

The main finding of the present study is to characterize the expression pattern of the components of the FGF23/KLOTHO system in human aortic vascular tissue and occlusive coronary thrombi. Specifically, our findings demonstrate the expression of KLOTHO and two cognate receptors for FGF23 (FGFR1 and FGFR3), whereas expression of FGF23 and FGFR4 was not detected. In addition, we also show that mRNA expression level of KLOTHO is directly and significantly correlated with expression levels of ADAM-17 and IL-10.

In the basis of previous results and the findings of the present work showing that human vascular tissue may be a target organ for FGF23, a putative role of FGF23-KLOTHO axis in cardiovascular disease is strongly suggested. Although at the present time, the actions of FGF23-KLOTHO system on human vascular tissue are unknown, one potential action would be a harmful FGF23-mediated effect through its binding to FGFRs in the vascular wall. FGF23 synthesis enhances in response to an increase in phosphate levels in order to avoid hyperphosphatemia and also, increased levels of FGF23 have been related to a reduction of Klotho expression and vitamin D synthesis. Thus, elevated FGF23 concentrations might act on the vascular wall inducing a local reduction of Klotho, a new agent able to ameliorate the calcifying vascular process, and vitamin D, a recognized important factor for cardiovascular health, which may result in vascular injury and cardiovascular disease.
This could be a very exciting novel regulation model that extends the target-organs for FGF23 action. Therefore, additional studies are warranted to determine whether the FGF23-KLOTHO axis modulates atherosclerosis development and progression through the regulation of mineral metabolism, or if this axis may play a direct role in vascular pathology.