The renin-angiotensin system (RAS) plays an important role in the development of atherosclerosis and cardiovascular diseases. Angiotensin II (AngII), the main mediator of this system, is highly expressed in the vascular wall. In the artery wall, Ang II promotes endothelial dysfunction and the development of an atherosclerotic plaque. For the prevention and treatment of cardiovascular diseases, statins and RAS inhibitors are used, which besides the primary effect on cholesterol and blood pressure reduction, also have antiinflammatory and antioxidant pleiotropic effects that lead to improvement in vascular function.
The aim of this study was to develop a cell model for the study of subtherapeutic effects of fluvastatin and valsartan on cellular RAS in primary human coronary artery endothelial cells (HCAEC). After the administration of active pharmaceutical ingredients, the cells were treated with serum amyloid A (SAA) and the effect of SAA and active pharmaceutical ingredients on the expression of selected genes of the RAS were determined.
We found that, contratry to expectations and literary sources, cellular RAS does not exist in HCAEC since there is no expression of precursor angiotensinogen (AGT) and enzymes that are involved in its conversion into active mediators of RAS. The results showed that SAA does not affect the expression of RAS components. The exception is the angiotensin converting enzyme (ACE), expression of which was even reduced by SAA. HCAEC express angiotenisn II type 1 receptor (AGTR1), which may be important if Ang II is not fully degraded after the receptor endocytosis and released intrucellularly where it binds to intracellular AGTR1 receptors. SAA acts proaterogenic as it increases the expression of the vascular cell adhesion molecule 1 (VCAM-1), cytokine interleukin 6 (IL-6), chemokine interleukin 8 (IL-8) and matrix metalloproteinase 1 (MMP1). On the other hand, fluvastatin has protective effects on endothelial cells, as it increases the expression of the enzyme endothelial nitric oxide synthase (NOS3) and reduces the expression of VCAM-1, IL-6 and IL-8. Furthermore our results also show that valsartan has a lower impact on the expression of selected genes than fuvastatin. Since the results for fluvastatin and combination of drugs are similar and the effects of valsartan on the expression of selected genes are small, we can conclude that these effects are result of the action of fluvastatin. Based on the results obtained, the combination of active substances does not show synergistic effects. The listed effects of SAA, fluvastatin and valsartan on HCAEC are most likely not mediated by cellular RAS, but are the result of the activation of other signaling pathways.