Medizinische Universität Graz Austria/Österreich - Forschungsportal - Medical University of Graz

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SHR Neuro Krebs Kardio Lipid Stoffw Microb

Mhatre, KN; Wakula, P; Klein, O; Bisping, E; Völkl, J; Pieske, B; Heinzel, FR.
Crosstalk between FGF23- and angiotensin II-mediated Ca²⁺ signaling in pathological cardiac hypertrophy.
Cell Mol Life Sci. 2018; 75(23):4403-4416 Doi: 10.1007/s00018-018-2885-x
Web of Science PubMed FullText FullText_MUG

Führende Autor*innen der Med Uni Graz: Heinzel Frank; Mhatre Ketaki Nitin
Co-Autor*innen der Med Uni Graz: Bisping Egbert Hubertus; Pieske Burkert Mathias; Wakula-Heinzel Paulina
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Abstract:: Heart failure (HF) manifestation and progression 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 HF and cardiovascular mortality. It is also a mediator of left-ventricular hypertrophy (LVH). In vivo, high circulating levels of FGF23 are associated with an altered systemic RAAS response. FGF23 is proposed to trigger pathological signaling mediated by Ca²⁺-regulated transcriptional pathways. In the present study, we investigated Ca²⁺-dependent signaling of FGF23 in ventricular cardiomyocytes and its association with angiotensin II (ATII). In neonatal rat ventricular myocytes (NRVMs), both ATII and FGF23 induced hypertrophy as observed by an increase in cell area and hypertrophic gene expression. Furthermore, FGF23 activates nuclear Ca²⁺-regulated CaMKII-HDAC4 pathway, similar to ATII. In addition to a global increase in cytoplasmic Ca²⁺, FGF23, like ATII, induced inositol 1, 4, 5-triphosphate (IP3)-induced Ca²⁺ release from the nucleoplasmic Ca²⁺ store, associated with cellular hypertrophy. Interestingly, ATII receptor antagonist, losartan, significantly attenuated FGF23-induced changes in Ca²⁺ homeostasis and cellular hypertrophy suggesting an involvement of ATII receptor-mediated signaling. In addition, application of FGF23 increased intracellular expression of ATII peptide and its secretion in NRVMs, confirming the participation of ATII. In conclusion, FGF23 and ATII share a common mechanism of IP3-nuclear Ca²⁺-dependent cardiomyocyte hypertrophy. FGF23-mediated cellular hypertrophy is associated with increased production and secretion of ATII by cardiomyocytes. These findings indicate a pathophysiological role of the cellular angiotensin system in FGF23-induced hypertrophy in ventricular cardiomyocytes.
Find related publications in this database (using NLM MeSH Indexing): Angiotensin II - metabolism; Angiotensin II - pharmacology; Animals -; Animals, Newborn -; Calcium - metabolism; Calcium Signaling - drug effects; Calcium-Calmodulin-Dependent Protein Kinase Type 2 - metabolism; Cardiomegaly - genetics; Cardiomegaly - metabolism; Cells, Cultured -; Fibroblast Growth Factors - blood; Fibroblast Growth Factors - metabolism; Fibroblast Growth Factors - pharmacology; Gene Expression - drug effects; Histone Deacetylases - metabolism; Myocytes, Cardiac - cytology; Myocytes, Cardiac - drug effects; Myocytes, Cardiac - metabolism; Rats -; Receptor, Angiotensin, Type 1 - metabolism
Find related publications in this database (Keywords): Cardio-renal axis; Ventricle cardiomyocytes; Localrenin-angiotensin system; Autocrine; Nuclear Ca2+ signaling