Abstract
Zinc is an essential trace element having various structural, catalytic and regulatory interactions with an estimated 3000 proteins. Zinc has drawn recent attention for its use, both as pure metal and alloyed, in arterial stents due to its biodegradability, biocompatibility, and low corrosion rates. Previous studies have demonstrated that zinc metal implants prevent the development of neointimal hyperplasia, which is a common cause of restenosis following coronary intervention. This suppression appears to be smooth muscle cell-specific, as reendothelization of the neointima is not inhibited. To better understand the basis of zinc's differential effects on rat aortic smooth muscle (RASMC) versus endothelial (RAENDO) cells, we conducted a transcriptomic analysis of both cell types following one-week continuous treatment with 5 µM or 50 µM zinc. This analysis indicated that genes whose protein products regulate mitochondrial functions, including oxidative phosphorylation and fusion/fission, are differentially affected by zinc in the two cell types. To better understand this, we performed Seahorse metabolic flux assays and quantitative imaging of mitochondrial networks in both cell types. Zinc treatment differently affected energy metabolism and mitochondrial structure/function in the two cell types. For example, both basal and maximal oxygen consumption rates were increased by zinc in RASMC but not in RAENDO. Zinc treatment increased apparent mitochondrial fusion in RASMC cells but increased mitochondrial fission in RAENDO cells. These results provide some insight into the mechanisms by which zinc treatment differently affects the two cell types and this information is important for understanding the role of zinc treatment in vascular cells and improving its use in biodegradable metal implants.
Highlights
Percutaneous coronary intervention is a common practice to establish revascularization during stenotic arterial disease
A decreasing gradient of smooth muscle cells near the implant surface [15,16,17]. These results suggest that zinc-based stents may function as a possible alternative to drug-eluting stents for the prevention of in-stent restenosis in vivo
We demonstrate that zinc treatment of endothelial cells results in a dose-dependent increase in mitochondrial fission, whereas smooth muscle cells demonstrate a dose-dependent increase in mitochondrial fusion
Summary
Percutaneous coronary intervention is a common practice to establish revascularization during stenotic arterial disease. Previous studies have evaluated the cellular response of rat aortic smooth muscle and endothelial cells for up to 24 h [6,10] While this approach may highlight cellular signaling pathways targeted by exogenous zinc, it does not model the more relevant physiological adaptation of cells exposed to a slowly degrading metal implant in vivo. RNA-seq analyses of rat aortic endothelial and smooth muscle cells in these experiments revealed significant effects of zinc on gene expression in both cell types, with a primarily mitochondrial response at low concentration (5 μM) and upregulation of proteins required for regulation of metal homeostasis at higher concentrations (50 μM). All statistical analyses were performed using GraphPad Prism version 9.1.0 (San Diego, CA)
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