Role of FGF23 in Acute Myocardial Infarction

The increasing prevalence of heart failure poses enormous challenges for health care systems worldwide. Despite state-of-the-art medical therapy, mortality and morbidity remain substantial. The discovery of additional mechanisms in disease progression in chronic heart failure and the identification of novel therapeutic targets would be highly desirable. The current proposal focusses on a novel link between cardiovascular pathophysiology and mineral homeostasis, namely a heart-bone-kidney signaling axis involving fibroblast growth factor-23 (FGF23).

FGF23 is a bone-derived hormone secreted by osteoblasts and osteocytes in response to vitamin D and increased phosphate in the extracellular fluid. Although it was initially described as a phosphaturic hormone, we recently found that FGF23 also has profound effects on sodium and volume regulation by directly upregulating the sodium chloride channel NCC in renal distal tubules in a Klotho-dependent fashion. Membrane-bound Klotho is the co-receptor of FGF23. Not only is Vitamin D essential for the maintenance of mineral homeostasis, it also plays an important part in cardiovascular function. FGF23 and vitamin D metabolism are closely linked, because the renal 1α-hydroxylase, the key enzyme controlling the production of the vitamin D, is tightly regulated by circulating FGF23. We recently found that circulating Fgf23 levels are profoundly up- and vitamin D hormone levels down-regulated after acute myocardial infarction (AMI) in rats and mice in a phosphate- and parathyroid hormone-independent manner. The mechanism leading to augmented FGF23 secretion post-MI is currently unknown, and will be explored in the current proposal. We hypothesize that increased circulating FGF23 post-AMI is a previously unrecognized pathophysiological factor causally linked to progression of cardiac disease. The proposed work addresses this novel heart – bone –kidney axis, and seeks to gain insights into the role of Fgf23 for disease progression in experimental AMI.

We aim to characterize the pathophysiological role of increased FGF23 signaling after AMI using blocking anti-FGF23 antibodies in wild type, vitamin D receptor (VDR) mutant mice with a non-functioning vitamin D receptor and in Klotho/VDR compound mutants. The experiments will reveal the pathophysiological role of elevated Fgf23 post-AMI, and will define the Klotho-dependent and –independent roles of Fgf23 on heart, renal sodium reabsorption and vitamin D production in this complex system. In addition, we seek to identify the cellular origin of Fgf23 and the mechanisms leading to increased Fgf23 serum levels post-AMI. Understanding the mechanisms may lead to new therapeutic possibilities to prevent the possibly untoward rise in circulating Fgf23 post-AMI. Combining pharmacological and genetic in vivo models with in vitro studies, the proposed work will explore the pathophysiological role of elevated Fgf23 post-AMI. The results may not only have very important clinical implications but will also significantly contribute to the development of the new field of cardio-osteology.



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