Rapamycin impairs endothelial cell function in human internal thoracic arteries.

Reineke, David Christian; Müller-Schweinitzer, Else; Winkler, Bernhard; Kunz, Donatina; Konerding, Moritz A; Grussenmeyer, Thomas; Carrel, Thierry; Eckstein, Friedrich S; Grapow, Martin T R (2015). Rapamycin impairs endothelial cell function in human internal thoracic arteries. European journal of medical research, 20, p. 59. I. Holzapfel 10.1186/s40001-015-0150-4

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BACKGROUND

Definitive fate of the coronary endothelium after implantation of a drug-eluting stent remains unclear, but evidence has accumulated that treatment with rapamycin-eluting stents impairs endothelial function in human coronary arteries. The aim of our study was to demonstrate this phenomenon on functional, morphological and biochemical level in human internal thoracic arteries (ITA) serving as coronary artery model.

METHODS

After exposure to rapamycin for 20 h, functional activity of ITA rings was investigated using the organ bath technique. Morphological analysis was performed by scanning electron microscopy and evaluated by two independent observers in blinded fashion. For measurement of endothelial nitric oxide synthase (eNOS) release, mammalian target of rapamycin (mTOR) and protein kinase B (PKB) (Akt) activation, Western blotting on human mammary epithelial cells-1 and on ITA homogenates was performed.

RESULTS

Comparison of the acetylcholine-induced relaxation revealed a significant concentration-dependent decrease to 66 ± 7 % and 36 ± 7 % (mean ± SEM) after 20-h incubation with 1 and 10 μM rapamycin. Electron microscopic evaluation of the endothelial layer showed no differences between controls and samples exposed to 10 μM rapamycin. Western blots after 20-h incubation with rapamycin (10 nM-1 μM) revealed a significant and concentration-dependent reduction of p (Ser 1177)-eNOS (down to 38 ± 8 %) in human mammary epithelial cells (Hmec)-1. Furthermore, 1 μM rapamycin significantly reduced activation of p (Ser2481)-mTOR (58 ± 11 %), p (Ser2481)-mTOR (23 ± 4 %) and p (Ser473)-Akt (38 ± 6 %) in ITA homogenates leaving Akt protein levels unchanged.

CONCLUSIONS

The present data suggests that 20-h exposure of ITA rings to rapamycin reduces endothelium-mediated relaxation through down-regulation of Akt-phosphorylation via the mTOR signalling axis within the ITA tissue without injuring the endothelial cell layer.

Item Type:

Journal Article (Original Article)

Division/Institute:

04 Faculty of Medicine > Department of Cardiovascular Disorders (DHGE) > Clinic of Cardiovascular Surgery

UniBE Contributor:

Reineke, David Christian; Winkler, Bernhard and Carrel, Thierry

Subjects:

600 Technology > 610 Medicine & health

ISSN:

0949-2321

Publisher:

I. Holzapfel

Language:

English

Submitter:

Daniela Huber

Date Deposited:

02 Feb 2016 15:06

Last Modified:

02 Feb 2016 15:06

Publisher DOI:

10.1186/s40001-015-0150-4

PubMed ID:

26104664

BORIS DOI:

10.7892/boris.75012

URI:

https://boris.unibe.ch/id/eprint/75012

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