Genetic Ablation of Fgf23 or Klotho Does not Modulate Experimental Heart Hypertrophy Induced by Pressure Overload

Abstract

Left ventricular hypertrophy (LVH) ultimately leads to heart failure in conditions of increased cardiac pre- or afterload. The bone-derived phosphaturic and sodium-conserving hormone fibroblast growth factor-23 (FGF23) and its co-receptor Klotho have been implicated in the development of uremic LVH. Using transverse aortic constriction (TAC) in gene-targeted mouse models, we examine the role of Fgf23 and Klotho in cardiac hypertrophy and dysfunction induced by pressure overload. TAC profoundly increases serum intact Fgf23 due to increased cardiac and bony Fgf23 transcription and downregulation of Fgf23 cleavage. Aldosterone receptor blocker spironolactone normalizes serum intact Fgf23 levels after TAC by reducing bony Fgf23 transcription. Notably, genetic Fgf23 or Klotho deficiency does not influence TAC-induced hypertrophic remodelling, LV functional impairment, or LV fibrosis. Despite the profound, aldosterone-mediated increase in circulating intact Fgf23 after TAC, our data do not support an essential role of Fgf23 or Klotho in the pathophysiology of pressure overload-induced cardiac hypertrophy.

Strength of Fibroblast Growth Factor 23 as a Cardiovascular Risk Predictor in Chronic Kidney Disease Weaken by ProBNP Adjustment

“…This concern has been founded upon the observation that hypertrophic and failing [20,23,28] hearts may directly produce FGF23, that particularly high FGF23 levels are found in patients with severe acute heart disease [38,39], and that patients chronically exposed to high FGF23 -such as patients with hypophosphatemic rickets/osteomalacia -do not regularly develop heart disease [40]. Experimentally, a direct role of FGF23 in the development of vascular calcification has largely been ruled out [41], and data on its contribution to left ventricular hypertrophy remains uncertain: even though several reports have suggested FGF23 to activate cardiomyocytes and induce their proliferation [8,9], later studies have questioned these findings [15][16][17][18][19][20]. Short-term results from CARE FOR HOMe have been published earlier [7].…”

“…Despite this early enthusiasm for such novel therapeutic interventions, certain caveats have recently arisen: Experimentally, independent study groups did not unanimously confirm a cardiotoxic effect of FGF23 [15][16][17][18][19], and latest rodent studies have implied that FGF23 may be a consequence rather than a cause of myocardial disease [20]. Epidemiologically, the majority of cohort studies that suggested an independent role of plasma FGF23 to predict adverse cardiovascular outcome dates back several years [3][4][5]7], when our understanding of FGF23 regulation was less comprehensive.…”

PTH, vitamin D, and the FGF‐23–klotho axis and heart: Going beyond the confines of nephrology

“…Neonatal cardiomyocytes treated with angiotensin II to induce cellular hypertrophy showed a smaller cell area and decreased β‐myosin heavy chain (βMHC) expression in the presence of klotho, supporting the idea that it protects against cardiac damage related to hypertrophy . However, no differences in hypertrophy were observed between klotho‐deficient mouse and wild‐type mice in a TAC model of cardiac hypertrophy …”

“…Studies using experimental models of direct cardiac damage have been very useful to test whether FGF‐23 is a pathophysiological factor causally linked to progression of cardiac dysfunction. Thus, transverse aortic constriction (TAC) in wild‐type mice, an experimental model of pressure overload‐induced cardiac hypertrophy, induced a strong increase in serum FGF‐23 levels that was accompanied by upregulation of cardiac but not bone FGF‐23 expression, demonstrating that the heart per se is able to express FGF‐23 under pressure overload conditions . Interestingly, the same study showed that TAC‐induced cardiac hypertrophy also developed in FGF‐23 knockout mice, indicating that FGF‐23 may not be an essential factor mediating pressure‐induced cardiac hypertrophy.…”

FGF23, Hypophosphatemia, and Emerging Treatments

“…Indeed it has been long argued that the increases in FGF23 are causal for cardiac hypertrophy, although via Klotho‐independent processes. However, recent studies using mouse models of FGF23 knockout and upregulation do not support this supposition, and individuals with primarily FGF23‐related hypophosphatemic bone disease do not consistently present with ventricular hypertrophy . As with CKD, the difference may be due to whether elevations of FGF23 are occurring during hyperphosphatemia or hypophosphatemia.…”