Expression of FGF23/KLOTHO system in human vascular tissue
Introduction
Fibroblast growth factor (FGF)-23 is a recently discovered phosphaturic hormone synthesized and secreted by bone cells, mainly osteoblasts. This hormone acts primarily on the kidney, where it induces phosphaturia and suppresses vitamin D synthesis, regulating phosphate homeostasis [1]. FGF23 belongs to a subgroup of the FGF ligand superfamily called endocrine FGFs [2], [3], which, unlike paracrine and/or autocrine FGFs, posses differential features in their binding domains that allow them to enter into systemic circulation, but also determine them to require one or more cofactors to activate FGF receptors (FGFRs). Thus, FGF23 has very low affinity to FGFRs and it requires Klotho to bind and activate the cognate FGFRs under physiological concentration [4].
Since most tissues express FGFRs, presence of Klotho determines FGF23 target organs. The cognate FGFRs activated in the presence of transmembrane cofactor Klotho are FGFR1, 3 and 4 [5], [6], [7]. This represents a novel mechanism for confining target organs in redundant ligand–receptor interactions [2]. Until now, the organs described to express Klotho are distal convoluted tubules in the kidney, choroid plexus in the brain and also parathyroid gland, placenta, ovary, testis, small intestine, prostate, and sinoatrial node of the heart [8], [2], [5], [9], [10].
Recent studies have reported that higher serum FGF23 levels, even within the normal range, are independently associated with impaired vasoreactivity and increased arterial stiffness [11]. Moreover, in patients with stable coronary artery disease, higher FGF23 has been demonstrated to be independently associated with cardiovascular events and mortality [12]. On the other hand, secreted form of Klotho protein, formed by proteolytic cleavage on the cell surface by membrane-anchored A Desintegrin and Metalloproteinases (ADAM)-17 and -10, may also function as a humoral factor [13], and has been potentially related to protective mechanism against endothelial dysfunction by upregulating the anti-inflammatory cytokine interleukin-10 (IL-10) in vascular tissue [14]. 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. Most of the works in this area have been done in vitro or in animal tissues, but the expression of FGF23, FGFRs and KLOTHO in human vascular tissue remains unproved. Therefore, we aimed to study the expression of members of the FGF23–KLOTHO axis in human aortic vascular tissue and also analyzed the expression of ADAM-17 and IL-10, factors related to KLOTHO functionality. In addition, we evaluated the expression of FGF23 and KLOTHO in coronary thrombi obtained from patients with acute coronary syndromes (ACS).
Section snippets
Patients
Thoracic aorta specimens were obtained from 44 consecutive patients (9 females, 35 males; mean age of 64.7 ± 9.3 years) who underwent elective cardiac surgery (coronary artery bypass surgery in 37 patients and replacement valvular surgery in 7 patients) at the Hospital Universitario de Canarias (Tenerife, Spain). Thrombus samples were collected using aspiration catheter from the site of coronary occlusion during primary percutaneous coronary intervention in two patients with ACS at the Cardiology
Expression of FGF23–KLOTHO axis components mRNA by RT-PCR
To analyze the expression of the components of the FGF23–KLOTHO axis (FGF23, KLOTHO and FGFRs) in human vascular tissue and thrombi, RT-PCR from cDNA reverse transcribed from extracted RNA was performed. FGF23 expression was not detected in any sample, whereas KLOTHO mRNA expression was demonstrated by obtaining an amplification product of the predicted size in all the specimens tested (Fig. 1). Regarding FGFRs, expression analysis in aortic tissue showed the presence of FGFR1, FGFR2 and FGFR3
Discussion
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. 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 was direct and significantly correlated with expression levels of ADAM-17 and IL-10. Finally, we show
Acknowledgments
This study was funded by Fondo de Investigación Sanitaria, Instituto de Salud Carlos III, Ministerio de Sanidad y Consumo (Ref. PI 07/0870). The authors of this manuscript have certified that they comply with the Principles of Ethical Publishing in the International Journal of Cardiology.
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