Abstract
BackgroundStatin drugs are one of the most commonly prescribed pharmaceuticals by physicians. By blocking the rate-limiting step in the cholesterol biosynthesis pathway, statins inhibit cholesterol synthesis, which benefits patient health. However, since many other important cellular processes are regulated within this pathway, they may also be influenced by statin therapy. These pleiotropic effects of statins have not been fully investigated, but are believed to positively influence endothelial cells (ECs), which line the vasculature in a confluent monolayer. Few studies have considered the effect of blood flow on ECs and how this may augment EC response to statins.MethodsIn this study, the effect of statin treatment on ECs is investigated for cells stimulated with tumor necrosis factor alpha (TNF-α), an inflammatory cytokine that promotes an atheroprone endothelium. Additionally, ECs are exposed to a physiologically relevant wall shear stress (WSS) of 12.5 dynes/cm2 using a three-dimensional tissue culture model to provide a realistic hemodynamic environment. ECs are analyzed for morphology using light microscopy as well as cytoskeletal structure and alignment using confocal microscopy. Statistical analysis is performed on the results using both the one-way analysis of variance with Bonferroni post-tests and the two-tailed t test.ResultsWe have shown that statin treatment caused cells to adapt to a rounded, atheroprone morphology, with a significantly higher shape index. Oppositely, TNF-α stimulation caused cells to elongate to an atheroprotective morphology, with a significantly lower shape index. WSS and TNF-α were unable to reverse any statin-induced cell rounding or F-actin disruption.ConclusionFurther work is therefore needed to determine why statin drugs cause cells to have an atheroprone morphology, but an atheroprotective genotype, and why TNF-α stimulation causes an atheroprotective morphology, but an atheroprone genotype. Despite the morphological changes due to statins or stimulation, ECs still respond to WSS. Understanding how statins influence ECs will allow for more targeted treatments for hypercholestemia and potentially other diseases.
Highlights
Despite improved treatment options available, cardiovascular diseases, such as atherosclerosis, remain a leading cause of death in North America [1]
TNF‐α stimulated endothelial cells (ECs) respond to wall shear stress (WSS) and elongate When ECs were stimulated with 10 ng/mL tumor necrosis factor alpha (TNF-α) at a WSS of 12.5 dynes/cm2, there was a significant decrease in shape index (SI) when compared to the non-stimulated, perfused control, Figure 2 (P < 0.001, one-way ANOVA with Bonferroni post-tests)
We have shown that both statin therapy and TNF-α stimulation induce changes in the cell, but that ECs still respond to WSS despite the statin-induced fragmentation
Summary
Despite improved treatment options available, cardiovascular diseases, such as atherosclerosis, remain a leading cause of death in North America [1]. There are other benefits to statin therapy that the decrease in cholesterol alone cannot explain, called pleiotropic effects [10, 12,13,14] These effects are believed to be regulated in side pathways of the cholesterol biosynthesis pathway [10, 15], which is responsible for cellular processes such as cellular movement, signaling, morphology, differentiation, and cytoskeletal remodeling [10, 16, 17]. Since many other important cellular processes are regulated within this pathway, they may be influenced by statin therapy These pleiotropic effects of statins have not been fully investigated, but are believed to positively influence endothelial cells (ECs), which line the vasculature in a confluent monolayer. Few studies have considered the effect of blood flow on ECs and how this may augment EC response to statins
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