Influence of Statin Use on Endothelial Function: From Bench to Clinics

Abstract

Endothelial dysfunction has been shown to be a prognostic factor for cardiovascular disease and improvement of endothelial dysfunction prevents cardiovascular event presentation. Endothelial dysfunction is associated to a reduced nitric oxide (NO) bioactivity, as a result of the impairment of NO synthesis/release by the endothelial NO synthase (eNOS) or by inactivation of NO. Endothelial dysfunction measurements are valuable surrogate markers to assess the effectiveness of interventions addressed to prevent or treat coronary heart disease (CHD). Dyslipemia and other cardiovascular risk factors promote endothelial dysfunction and life style changes and pharmacological treatment, particularly HMG-CoA reductase inhibitors (statins), have shown early improve of endothelial-dependent vasomotion. Statins efficiently reduce plasma LDL cholesterol, an effect that may account for their beneficial effect on endothelial function, but they also reduce cellular levels of isoprenoid compounds relevant for the bioavailability of NO. Statins restore NO production by several mechanisms, including up-regulation of eNOS mRNA and protein levels and preservation of NO inactivation by reactive oxygen species (ROS). These effects are mediated, at least in a part, through mechanisms independent of their lipid lowering effect (pleiotropic effects). In this article we discuss the relevance of endothelium-dependent effects on the early and delayed clinical benefit of statins, as well as the multiple ways by which statins may restore endothelial function acting not only on the endothelium but also on endothelial progenitor cells (EPC), which likely could contribute to both ischemia-induced neovascularization and endothelial regeneration after injury.

High pre-transplant serum nitrate levels predict risk of acute steroid-refractory graft-versus-host disease in the absence of statin therapy

“…Statins have been shown to exert pleiotropic, concentration-dependent effects, including eNOS induction and vessel stabilization. 16,37,38 Recently, we reported that intestinal biopsy findings of patients with refractory haematologica | 2014; 99(3) Figure 1. (A) Serum nitrate levels measured prior to allogeneic SCT predict steroid-refractory GVHD and NRM.…”

“…14 Statins lower cholesterol levels by inhibiting 3-hydroxy-3-methyl-CoA (HMG-CoA) reductase and are, therefore, used to prevent complications of arteriosclerotic diseases. Besides protective effects on endothelial cells, 15,16 statins also modulate the immune system. 17,18 This has led several investigators to test statins in the context of allogeneic SCT, but the results have been inconsistent.…”

Role of DNA damage in atherosclerosis—Bystander or participant?

“…This effectively results in lower levels of oxidised LDL in the vessel, reducing both the production of damaging ROS, and the subsequent oxidative DNA damage caused by these molecules. As additional benefit to their lipid-lowering effects, statins have been shown to participate in modulating other processes involved in the development of atherosclerosis, including improving endothelial function, modulating the inflammatory response, maintaining plaque stability and preventing the formation of thrombus in the vessel [80,81].…”

Clinical Pharmacology and Vascular Risk

“…These effects are mediated, at least in a part, through mechanisms independent of their lipid lowering effect (pleiotropic effects). The relevance of endotheliumdependent effects on the early and delayed clinical benefit of statins, as well as the multiple ways by which statins may restore endothelial function acting not only on the endothelium but also on endothelial progenitor cells, which probably could contribute to both ischemia-induced neovascularization and endothelial regeneration after injury [62].…”