Abstract
The present study was aimed at investigating the detailed functions of atorvastatin, a lipid-lowering agent, in the pathogenesis of coronary slow flow (CSF), a clinical disease characterized by delayed angiographic coronary opacity without obstructive coronary disease. In the present study, we successfully identified isolated endothelial progenitor cells (EPCs) from the peripheral blood of patients with CSF. Their vascular endothelial growth factor-A (VEGFA) protein levels were determined using immunoblotting analyses. We determined cell viability using MTT assays, cell migration capacity using Transwell assays, and the angiogenic capacity using a tube formation assay. The target association between miR-221 and VEGFA was validated with a luciferase reporter assay. Atorvastatin treatment increased EPC VEGFA protein levels, proliferation, migration, and angiogenesis. miR-221 expression was down-regulated after atorvastatin treatment; miR-221 overexpression exerted an opposing effect to atorvastatin treatment on VEGFA protein, EPC proliferation, migration, and angiogenesis. The protective effects of atorvastatin treatment on VEGFA protein and EPCs could be significantly suppressed by miR-221 overexpression. miR-221 directly bound the VEGFA 3′UTR to inhibit its expression. In conclusion, atorvastatin improves the cell proliferation, migration, and angiogenesis of EPCs via the miR-221/VEGFA axis. Thus, atorvastatin could be a potent agent against CSF, pending further in vivo and clinical investigations.
Highlights
Coronary slow flow (CSF) is a clinical disease characterized by delayed angiographic coronary opacity without obstructive coronary disease [1,2] and is often associated with chest pain
We assessed the effects of atorvastatin on the angiogenic capacity of endothelial progenitor cell (EPC) in vitro and found that the tube number was increased in atorvastatin-treated EPCs (Figure 1F)
These data indicate that atorvastatin treatment could improve growth, and the migratory and angiogenic capacity of EPCs, probably in a vascular endothelial growth factor-A (VEGFA)-related manner
Summary
Coronary slow flow (CSF) is a clinical disease characterized by delayed angiographic coronary opacity without obstructive coronary disease [1,2] and is often associated with chest pain. CSF has been associated with a number of clinical features, including cardiac ischemia, life-threatening cardiac arrhythmias, and heart-related sudden death [3,4]. CSF has been associated with inflammation, microvascular disease, blood vessel endothelium dysfunction, impaired glucose tolerance, and other diseases [5], but its pathogenesis remains unclear. Many studies have shown that a long-term administration of atorvastatin could provide beneficial effects to the coronary blood flow and coronary blood reserve in patients with CSF [8,9]. Short-term lipid-lowering therapy (atorvastatin) could promote coronary flow reserve and coronary microvascular function [8]. The potential mechanisms of atorvastatin’s action on CSF remain largely unknown
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