High Magnesium and Sirolimus on Rabbit Vascular Cells—An In Vitro Proof of Concept

Giorgia Fedele,Laura Locatelli,Sara Castiglioni,Jeanette A Maier

doi:10.3390/ma14081970

Abstract

Drug-eluting bioresorbable scaffolds represent the last frontier in the field of angioplasty and stenting to treat coronary artery disease, one of the leading causes of morbidity and mortality worldwide. In particular, sirolimus-eluting magnesium-based scaffolds were recently introduced in clinical practice. Magnesium alloys are biocompatible and dissolve in body fluids, thus determining high concentrations of magnesium in the local microenvironment. Since magnesium regulates cell growth, we asked whether high levels of magnesium might interfere with the antiproliferative action of sirolimus. We performed in vitro experiments on rabbit coronary artery endothelial and smooth muscle cells (rCAEC and rSMC, respectively). The cells were treated with sirolimus in the presence of different concentrations of extracellular magnesium. Sirolimus inhibits rCAEC proliferation only in physiological concentrations of magnesium, while high concentrations prevent this effect. On the contrary, high extracellular magnesium does not rescue rSMC growth arrest by sirolimus and accentuates the inhibitory effect of the drug on cell migration. Importantly, sirolimus and magnesium do not impair rSMC response to nitric oxide. If translated into a clinical setting, these results suggest that, in the presence of sirolimus, local increases of magnesium concentration maintain normal endothelial proliferative capacity and function without affecting rSMC growth inhibition and response to vasodilators.

Highlights

Coronary artery disease exacts a very high toll in terms of morbidity and mortality all over the world [1]
The Effect of Sirolimus and Mg on rCAEC Growth, Migration and Morphology rCAEC were seeded at low density and cultured in the presence of 2, 10 and 50 ng/mL
We found that culture for 72 h with sirolimus inhibits rSMC migration (Figure 4B). 3 mM Mg alone reduces migration compared to 1 mM Mg, in accordance with previous reports [8], and does not interfere with the inhibitory effect of sirolimus

Summary

Introduction

Coronary artery disease exacts a very high toll in terms of morbidity and mortality all over the world [1]. Antiproliferative drug eluting stents were generated and percutaneous coronary intervention involving these devices is widely utilized to treat artery stenosis and prevent re-stenosis [3,4]. The last frontier for coronary stenting was the development of bioresorbable scaffolds (BRS), which provide transient vessel support and are gradually dissolved to avoid the permanent caging of the vessel, granting the restoration of vasomotion [5]. In this field, magnesium (Mg) alloys raised major interest because of their mechanical and biological features [6]. Mg is beneficial for the arteries and, in particular, it positively impacts endothelial function by preventing oxidative stress and

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Results

Conclusion