Abstract: SA-PO987
Cardiac-Specific FGF23 Knockout Leads to Increased Cardiovascular Risk
Session Information
- Hypertension and CVD: Mechanisms - II
October 27, 2018 | Location: Exhibit Hall, San Diego Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: Hypertension and CVD
- 1403 Hypertension and CVD: Mechanisms
Authors
- Leifheit-Nestler, Maren, Hannover Medical School, Hannover, Germany
- Schmaltz, Saskia, Hannover Medical School, Hannover, Germany
- Szaroszyk, Malgorzata, Hannover Medical School, Hannover, Germany
- Richter, Beatrice, The University of Alabama at Birmingham, Birmingham, Alabama, United States
- Heineke, Joerg, Medical Faculty Mannheim of Heidelberg University, Mannheim, Germany
- Haffner, Dieter, Hannover Medical School, Hannover, Germany
Background
Patients with CKD have an higher risk for cardiovascular disease (CVD) and mortality associated with increased levels of FGF23. Recent studies indicate that FGF23 is expressed by cardiac myocytes and activates the calcineurin/NFAT pathway via activation of FGFR4 in the heart and may contribute to the development of LVH. We hypothesized that cardiac FGF23 is a modifier of CVD risk in mice.
Methods
To this aim we generated a mouse model with a cardiac myocyte-specific FGF23 knockout (FGF23-KO) in the C57BL/6 background using the Cre/loxP system. we evaluated the impact of cardiac FGF23 on the heart. Cardiovascular outcome in FGF23-KO receiving a standard diet was compared to wild-type littermates (WT) during an observational period of up-to 6-months. In addition, we compared pressure overload-induced cardiac hypertrophy induced by transverse aortic constriction (TAC) in 8-weeks old FGF23-KO and WT mice.
Results
Body weight, heart weight, tibia length and parameter of mineral metabolism including FGF23 synthesis in bone and plasma intact FGF23 levels did not differ between FGF23-KO mice and WT group. FGF23-KO mice showed significantly increased mortality compared to WT associated with enhanced end-diastolic LV volume and stroke volume examined by cardiac magnetic resonance imaging (cMRI). On molecular level, pro-hypertrophic and pro-fibrotic markers ANP, BNP, collagen 1, TGF-β and CTGF were enhanced in heart tissue of FGF23-KO mice and local cardiac renin-angiotensin-aldosterone system was activated compared to WT mice. As expected, heart function was impaired in WT mice 2 weeks after TAC compared with Sham along with increased relative heart weight, cardiac myocyte size and the induction of pro-hypertrophic genes and bone and cardiac FGF23 synthesis. Interestingly, FGF23-KO mice after TAC showed the same heart phenotype like WT TAC with exception of cardiac FGF23 synthesis. Moreover, cMRI revealted increased end-systolic LV volume and systolic LV diameter in FGF23-KO TAC compared to WT TAC mice.
Conclusion
In conclusion, cardiac myocyte-specific FGF23 knockout leads to impaired heart function and increased mortality in mice and results in increased CVD in the high pressure-induced hypertrophic mouse model. Thus our data suggest a physiological role of cardiac FGF23 in heart function and adaption to pressure overload.