Abstract: SA-PO988
Cardiac-Specific Overexpression of FGF23 Fails to Induce Cardiac Hypertrophy in Mice Without CKD
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
- Wagner, Miriam, Hannover Medical School, Hannover, Germany
- Richter, Beatrice, The University of Alabama at Birmingham, Birmingham, Alabama, United States
- Haffner, Dieter, Hannover Medical School, Hannover, Germany
Background
High circulating and cardiac FGF23 levels are associated with increased risk of cardiovascular events and all cause mortality in CKD patients. We showed on molecular level that FGF23 stimulates hypertrophic growth of isolated cardiac myocytes in the absence of klotho via activation of FGFR4/calcineurin/NFAT pathway leading to left ventricular hypertrophy (LVH). It is still a matter of debate if elevated FGF23 results in LVH under healthy conditions, e.g. in the absence of CKD.
Methods
By generating a mouse model with cardiac specific overexpression of FGF23 using cardiovascular gene transfer with an adeno-associated virus expressing FGF23 (AAV-FGF23) under the control of the cardiac troponin T promotor, we investigated the pro-hypertrophic properties of cardiac FGF23 in C57BL/6N wild-type mice.
Results
The detection of AAV expression within various organs verified the specific accumulation of AAV-FGF23 in the heart. Cardiac Fgf23 mRNA expression was 2,000-fold increased in AAV-FGF23-treated mice compared to controls and immunoblot analysis point out that the cardiac FGF23 protein was full-length biologically active. This was further confirmed by enhanced cardiac and plasma intact FGF23 levels in AAV-FGF23 mice. Parameters of mineral metabolism and renal expression of klotho did not differ between AAV-FGF23 and controls, whereas NaPi2a and NaPi2c mRNA levels were significantly reduced. Although, AAV-FGF23-treated mice showed a moderate induction of cardiac Fgfr4 mRNA expression, relative heart weight and cardiac myocyte size did not differ between both groups and pro-hypertrophic NFAT target genes Rcan1, Trpc6, b-MHC, and ANP remained unchanged. Moreover, BNP levels were even significantly reduced in AAV-FGF23 mice compared to controls. Cardiac MRI analysis demonstrated no impairment of heart function in AAV-FGF23 mice but echocardiography studies showed significant increased stroke volume and cardiac output, which might be due to increased cardiac preload and/or enhanced contractility.
Conclusion
In conclusion, AAV-FGF23 induces the expression of full-length biological active FGF23 in the heart but fails to induce LVH under healthy conditions, suggesting that additional factors associated with CKD, e.g. klotho deficiency or high phosphate load, are necessary for FGF23 to tackle the heart.