The mineralocorticoid receptor leads to increased expression of EGFR and T-type calcium channels that support HL-1 cell hypertrophy

Abstract

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.

EGFR inhibition led ROCK activation enhances desmosome assembly and cohesion in cardiomyocytes

“…Vice versa, SRC can be activated by EGFR (Wilde et al, 1999). In the heart, EGFR was found to play a crucial role in cell metabolism, proliferation, cell survival, as well as hypertrophy and remodeling (Stroedecke et al, 2021). EGFR inhibition can lead to heart failure in the healthy heart, and a total knockout of the receptor can lead to severe hypertrophy and hypotension (Schreier et al, 2013, Kenigsberg et al, 2017, Guo et al, 2021).…”

Importance of Micromilieu for Pathophysiologic Mineralocorticoid Receptor Activity—When the Mineralocorticoid Receptor Resides in the Wrong Neighborhood

“…Cardiac arrhythmias are also frequent complications during aging. It was demonstrated in murine HL-1 atrial myocytes that aldosterone/MR increases the expression of Cacna1h, which may augment intracellular calcium concentrations and facilitate arrhythmias [ 64 ].…”

EGFR inhibition leads to enhanced desmosome assembly and cardiomyocyte cohesion via ROCK activation

“…Vice versa, SRC can be activated by EGFR (13). In the heart, EGFR was found to play a crucial role in cell metabolism, proliferation, cell survival, as well as hypertrophy and remodeling (14). EGFR inhibition can lead to heart failure in the healthy heart, and a total knockout of the receptor can lead to severe hypertrophy and hypotension (15)(16)(17).…”