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http://dx.doi.org/10.25673/57111
Titel: | The mineralocorticoid receptor leads to increased expression of EGFR and T-type calcium channels that support HL-1 cell hypertrophy |
Autor(en): | Stroedecke, Katharina Meinel, Sandra Markwardt, Fritz Kloeckner, Udo Straetz, Nicole Quarch, Katja Schreier, Barbara Kopf, Michael Gekle, Michael Grossmann, Claudia |
Erscheinungsdatum: | 2021 |
Art: | Artikel |
Sprache: | Englisch |
Zusammenfassung: | The EGF receptor (EGFR) has been extensively studied in tumor biology and recently a role in cardiovascular pathophysiology was suggested. The mineralocorticoid receptor (MR) is an important effector of the renin–angiotensin–aldosterone-system and elicits pathophysiological effects in the cardiovascular system; however, the underlying molecular mechanisms are unclear. Our aim was to investigate the importance of EGFR for MR-mediated cardiovascular pathophysiology because MR is known to induce EGFR expression. We identified a SNP within the EGFR promoter that modulates MR-induced EGFR expression. In RNA-sequencing and qPCR experiments in heart tissue of EGFR KO and WT mice, changes in EGFR abundance led to differential expression of cardiac ion channels, especially of the T-type calcium channel CACNA1H. Accordingly, CACNA1H expression was increased in WT mice after in vivo MR activation by aldosterone but not in respective EGFR KO mice. Aldosterone- and EGF-responsiveness of CACNA1H expression was confirmed in HL-1 cells by Western blot and by measuring peak current density of T-type calcium channels. Aldosterone-induced CACNA1H protein expression could be abrogated by the EGFR inhibitor AG1478. Furthermore, inhibition of T-type calcium channels with mibefradil or ML218 reduced diameter, volume and BNP levels in HL-1 cells. In conclusion the MR regulates EGFR and CACNA1H expression, which has an effect on HL-1 cell diameter, and the extent of this regulation seems to depend on the SNP-216 (G/T) genotype. This suggests that the EGFR may be an intermediate for MR-mediated cardiovascular changes and that SNP analysis can help identify subgroups of patients that will benefit most from MR antagonists. |
URI: | https://opendata.uni-halle.de//handle/1981185920/59062 http://dx.doi.org/10.25673/57111 |
Open-Access: | ![]() |
Nutzungslizenz: | ![]() |
Sponsor/Geldgeber: | Publikationsfonds MLU |
Journal Titel: | Scientific reports |
Verlag: | Macmillan Publishers Limited, part of Springer Nature |
Verlagsort: | [London] |
Band: | 11 |
Originalveröffentlichung: | 10.1038/s41598-021-92284-y |
Enthalten in den Sammlungen: | Open Access Publikationen der MLU |
Dateien zu dieser Ressource:
Datei | Beschreibung | Größe | Format | |
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s41598-021-92284-y.pdf | 3.09 MB | Adobe PDF | ![]() Öffnen/Anzeigen |