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 1a- 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.

In the current project, we have further explored the pathophysiological role of fibroblast growth factor-23 (FGF23) in experimental mouse models of myocardial infarction (MI) and left ventricular hypertrophy. FGF23 is not a growth factor as suggested by its name, but rather a hormone secreted from bone cells in response to elevated extracellular phosphate and vitamin D. At low concentrations, binding of FGF23 to fibroblast growth factor receptors on target cells requires the concomitant expression of the co-receptor protein Klotho. At high concentrations, FGF23 can bind to FGF receptors Klotho-independently. It is well known that FGF23 downregulates reabsorption of phosphate, and inhibits the synthesis of the vitamin D hormone in the kidney. In addition, data from other research groups suggested that FGF23 may be involved in the development of cardiac hypertrophy by a direct, Klotho-independent action on the heart. In this project, we found that bony FGF23 secretion is upregulated after MI and experimental left ventricular hypertrophy induced by pressure overload in a phosphate independent manner. Hence, the heart problem is associated with augmented secretion of FGF23 in bone. Our experiments revealed that the upregulation of circulating FGF23 hormone after cardiac lesions is mediated through increased aldosterone secretion, a hormone originating from the adrenal cortex. To further explore the role of FGF23 and Klotho in heart function we induced MI or left ventricular hypertrophy in mouse models globally deficient in Fgf23 and Klotho, or in mouse models characterized by cardiac-specific deletion of FGF23. In mice globally deficient in Fgf23 and Klotho, we found that absence of Fgf23 signaling improves cardiac remodeling and contractile function following experimental MI through the regulation of cardiac pro-inflammatory and pro-fibrotic signaling pathways. However, the development of left ventricular hypertrophy induced by pressure overload was not influenced by the absence of Fgf23 and Klotho in global knockout mice. Taken together, our data suggest that FGF23 signaling may not play an essential role in the development of left ventricular hypertrophy induced by pressure overload, but that FGF23 may act as a pro-inflammatory factor in the strained myocardium after MI.