Proceedings of The Physiological Society

Europhysiology 2018 (London, UK) (2018) Proc Physiol Soc 41, PCB372

Poster Communications

The Epidermal growth factor receptor mediates cardiac hypertrophy and structural associated gene expression alteration in the aorta of diabetes mellitus type II mice.

C. Stern1, B. Schreier1, S. Rabe1, S. Mildenberger1, M. Gekle1

1. Julius Bernstein Insitute for Physiology, Martin Luther University Halle-Wittenberg, Halle, Saxony-Anhalt, Germany.


In the industrialized society incidence of diabetes mellitus type II (DMT2) increases, probably due to unbalanced lifestyle comprising an excess of fatty foods and insufficient physical exercise. DMT2 is associated with cardiovascular complications, yet the underlying mechanisms are incompletely understood. During the last years the importance of the epidermal growth factor receptor (EGFR) in the cardiovascular system has been recognized, besides its well-known role in embryo- and tumorigenesis. In vascular smooth muscle cells (VSMC) e.g. the EGFR is needed for an appropriate vasoconstrictive response upon angiotensin II stimulation. Additionally, increased EGFR phosphorylation and pressure-induced myogenic tone in mesenteric arteries was reported in DMT2 mice, which could be attenuated by EGFR inhibition. To reveal the role of EGFR in cardiovascular pathophysiology associated with DMT2, our group established a mouse model with an inducible EGFR knock out (KO) in VSMCs and fed these, as well as wild type (WT) mice for 18 weeks either with a high fat diet (HFD, 5241.255kcal/kg) to induce DMT2 or standard chow (SD, 3188.487kcal/kg). Afterwards mice were sacrificed and morphology of organs was analyzed using formalin-fixed-paraffin embedded tissue sections of heart and kidney stained with Sirius Red (SR) and periodic acid Schiff (PAS). Next generation sequencing (NGS) and quantitative PCR of aortic tissue were performed to detect EGFR dependent gene expression. During the observation period the HFD mice gained more weight (SD: Δ66%, HFD: Δ107%) and blood glucose levels was increased (not fasted, SD: 7.9mmol/l, HFD: 9.7mmol/l) compared to SD mice. No difference between the genotypes could be observed, indicating that this model is a versatile tool to study the impact of EGFR on cardiovascular damages caused by DMT2. As expected an increased kidney weight in HFD mice compared to SD were detectable (SD: 362mg, HFD: 398mg), however lung weight was unaffected. Both genotypes displayed signs of HFD induced increased renal artery lumen (SD: 846µm2, HFD: 1864µm2), and glomerular sclerosis (sclerotic score SD: 2.5, HFD: 2.8). Interestingly an EGFR dependent cardiac hypertrophy under HFD conditions was detectable. NGS followed by high stringency gene set enrichment analyses (GESA) revealed an EGFR dependent upregulation of genes involved in extracellular matrix formation in the aortas of DMT2 mice. In conclusion, EGFR in VSMCs mediates DMT2 induced cardiac hypertrophy and gene expression in the aorta, this might lead to an altered functional response in blood vessels. Therefore inhibiting the EGFR might be an interesting approach in DMT2 treatment, although this opportunity needs to be investigated further.

Where applicable, experiments conform with Society ethical requirements