Medizinische Universität Graz Austria/Österreich - Forschungsportal - Medical University of Graz
Gewählte Publikation:
Mhatre, K.
Crosstalk between FGF23- and Angiotensin II-mediated Ca2+ signaling in pathological cardiac hypertrophy.
PhD-Studium (Doctor of Philosophy); Humanmedizin; [ Dissertation ] Graz Medical University; 2018. pp. 157
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- Autor*innen der Med Uni Graz:
- Mhatre Ketaki Nitin
- Betreuer*innen:
- Bisping Egbert Hubertus
- Groschner Klaus
- Altmetrics:
- Abstract:
- Heart failure (HF) manifestation and development are driven by systemic activation of neuroendocrine signaling cascades, such as the renin-angiotensin-aldosterone system (RAAS). Fibroblast growth factor 23 (FGF23), an endocrine hormone, is linked to chronic kidney disease which is a prominent co-morbidity in HF. It is also shown to be a mediator of left ventricular hypertrophy (LVH). In vivo, high circulating levels of FGF23 are associated with an altered systemic RAAS response. FGF23 is suggested to trigger pathological signaling mediated by Ca2+-regulated transcriptional pathways. In the present study, we investigated Ca2+-dependent signaling of FGF23 and its connection with angiotensin II (ATII) in cardiomyocytes (CM). In neonatal rat ventricular myocytes (NRVMs), both ATII and FGF23-induced hypertrophy as observed by a rise in the cell area and hypertrophic gene expression. In addition to a global increase in cytoplasmic Ca2+, FGF23, like ATII, triggered inositol 1, 4, 5-triphosphate (IP3)-dependent Ca2+ release (IICR) from the nucleoplasmic Ca2+ store. This local nuclear Ca2+ release is associated with cellular hypertrophy via activation of Ca2+-calmodulin(CaM)- calcium/calmodulin-dependent protein kinase II (CaMKII) – histone-deacetylases 4 (HDAC4) pathway. FGF23 treatment indeed induced nuclear Ca2+-regulated CaMKII – HDAC4 hypertrophic pathway, as is observed for ATII treatment. Interestingly, ATII receptor antagonist, losartan significantly attenuated FGF23-induced alterations in Ca2+ homeostasis and induction of cellular hypertrophy suggesting an involvement of ATII receptor-mediated signaling. Additionally, application of FGF23 increased intracellular expression of ATII peptide and its secretion in CMs, confirming the involvement of ATII. In this study, our findings suggest that FGF23 acutely increases IP3-dependent intracellular nuclear calcium and ATII levels and further its secretion in CMs. These factors may be pivotal for cellular hypertrophy observed with sustained stimulation by FGF23. These findings indicate a pathophysiological role of the cellular angiotensin system in FGF23-induced hypertrophy in ventricular CMs(Mhatre et al. 2018).