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Abstract: TH-OR11

Heparin Aggravates Cardiac Injury in Animal Models with High FGF-23

Session Information

Category: Bone and Mineral Metabolism

  • 401 Bone and Mineral Metabolism: Basic

Authors

  • Kentrup, Dominik, The University of Alabama at Birmingham, Birmingham, Alabama, United States
  • Yanucil, Christopher, The University of Alabama at Birmingham, Birmingham, Alabama, United States
  • Osis, Gunars, The University of Alabama at Birmingham, Birmingham, Alabama, United States
  • Campos, Isaac D., The University of Alabama at Birmingham, Birmingham, Alabama, United States
  • Czaya, Brian A., The University of Alabama at Birmingham, Birmingham, Alabama, United States
  • Heitman, Kylie, The University of Alabama at Birmingham, Birmingham, Alabama, United States
  • Faul, Christian, The University of Alabama at Birmingham, Birmingham, Alabama, United States
Background

It has been assumed that fibroblast growth factor (FGF) 23 as an endocrine FGF family member has low affinity for heparin, and instead requires klotho, a transmembrane protein, as a co-receptor on specific target cells. However, we and others have shown that elevated FGF23 levels can specifically activate FGFR4 in cardiac myocytes lacking klotho and thereby induce cardiac hypertrophy in animal models of chronic kidney disease (CKD). We have recently found that heparin does act as a FGF23 co-receptor by mediating FGF23 binding mainly to FGFR4 and thereby increases the pathologic actions of FGF23 on cultured cardiac myocytes. Here, we determine the in vivo relevance of these findings by studying the cardiac effects of heparin injections in three different mouse models with elevated serum FGF23 levels.

Methods

First, 12-week old, male BALB/cJ mice received serial i.v. injections of isotonic saline, heparin, FGF23, or FGF23 and heparin combined twice daily for 5 consecutive days. Second, 4-week old Alport mice (Col4a3tm1Dec), received serial i.v. injections of saline or heparin 3 times per week for 6 weeks. Third, 5-week old BALB/cJ mice on either 0.2% adenine diet or control chow were injected with either saline or heparin 3 times per week for 10 weeks. At the end of the experiment, echocardiographic analysis was performed, and tissue and serum were isolated for further analysis.

Results

Administration of heparin worsened cardiac outcomes in all three animal models. Compared with saline and FGF23 injections, BALB/cJ mice receiving FGF23 and heparin in combination developed a significant increase in heart weight / tibia length ratio, as well as in left ventricular (LV) mass and epicardial area. Alport mice receiving heparin injections showed increased heart weight / body weight ratios, LV mass and cardiac myocyte area, compared to wildtype littermates and Alport mice receiving saline. In addition, BALB/cJ mice on the adenine diet showed increased heart weight / body weight ratios and cardiac myocyte area when heparin was administered.

Conclusion

Our animal studies suggest that frequent heparin injections in individuals with elevated serum FGF23 levels, as the case in end-stage renal disease patients receiving hemodialysis, might contribute to adverse cardiac outcomes and high mortality.

Funding

  • NIDDK Support