Statins have antiproliferative and anti-tumoral effects in MCF-7 cells. We determined the effect of statins upon MCF-7 cell cycle, toxicity, cell death, reactive oxygen species (ROS) production and mitochondrial membrane potential. Fluvastatin, simvastatin and atorvastatin inhibited cell proliferation. Antiproliferation was associated with a decrease in the DNA synthesis and a cell cycle arrest in the G1 and G2/M phases. A loss in the mitochondrial membrane potential was observed with fluvastatin. Statins induced increase in ROS production that was associated with cell death, which was abrogated by the antioxidant NAC. Our results suggest that the cytotoxic effect observed is mediated by an oxidative stress.

BackgroundIn animal models of pulmonary arterial hypertension (PAH), angiotensin converting enzyme type 2 (ACE2) and Angiotensin 1–7 [Ang-(1–7)] have been shown to have vasodilatory, anti-proliferative, anti-fibrotic and anti-hypertrophic properties. However, the status and role of the ACE2-Ang-(1–7) axis in human PAH is incompletely understood.MethodsWe studied 85 patients with a diagnosis of PAH of distinct etiologies. Fifty-five healthy blood donors paired for age and sex served as controls. Blood samples were obtained from the pulmonary artery in patients with PAH during right heart catheterisation. Peripheral blood was obtained for both groups. Ang-(1–7) and angiotensin II (AngII) were measured by zone capillary electrophoresis. Aldosterone, Angiotensin-(1–9), Angiotensin A, (Ang-A) and ACE2 were measured by ELISA, and ACE2 activity was determined enzymatically.ResultsOf the 85 patients, 47 had idiopathic PAH, 25 had PAH-associated with congenital heart disease, and 13 had PAH-associated with collagen vascular disease. Compared to controls, patients with PAH had a higher concentration of AngII [(1.03(IQR 0.72–1.88) versus 0.19(IQR 0.10–0.37)pmoles·mL−1;p<0.001)] and of aldosterone [(88.7(58.7–132) versus 12.9(9.55–19.9)ng·dL−1;p<0.001)]. Conversely, PAH patients had a lower concentration of Ang-(1–7) than controls [(0.69(0.474–0.91) versus 4.07(2.82–6.73)pmoles·mL−1;p<0.001)], and a lower concentration of Ang-(1–9), and Ang-A. Similarly, the ACE2 concentration was higher than in controls [(8.7(5.35–13.2) versus 4.53(1.47–14.3)ng·mL−1;p=0.011)], whereas the ACE2 activity was significantly reduced [(1.88(1.08–2.81) versus 5.97(3.1–17.8)nmoles·mL−1;p<0.001)]. No significant differences were found among the three different etiologic forms of PAH.ConclusionsThe AngII-ACE2-Ang- (1–7) axis appears to be altered in human PAH and we propose that this imbalance, in favour of AngII, plays a role in the pathogenesis of the severe PAH. Further mechanistic studies are warranted.

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Reverse cholesterol transport (RCT) is considered as the most important antiatherogenic role of high-density lipoproteins (HDL), but interventions based on RCT have failed to reduce the risk of coronary heart disease. In contrast to RCT, important evidence suggests that HDL deliver lipids to peripheral cells. Therefore, in this paper, we investigated whether HDL could improve endothelial function by delivering lipids to the cells. Internalization kinetics using cholesterol and apolipoprotein (apo) AI fluorescent double-labeled reconstituted HDL (rHDL), and human dermal microvascular endothelial cells-1 (HMEC-1) showed a fast cholesterol influx (10 min) and a slower HDL protein internalization as determined by confocal microscopy and flow cytometry. Sphingomyelin kinetics overlapped that of apo AI, indicating that only cholesterol became dissociated from rHDL during internalization. rHDL apo AI internalization was scavenger receptor class B type I (SR-BI)-dependent, whereas HDL cholesterol influx was independent of SR-BI and was not completely inhibited by the presence of low-density lipoproteins (LDL). HDL sphingomyelin was fundamental for intercellular adhesion molecule-1 (ICAM-1) downregulation in HMEC-1. However, vascular cell adhesion protein-1 (VCAM-1) was not inhibited by rHDL, suggesting that components such as apolipoproteins other than apo AI participate in HDL’s regulation of this adhesion molecule. rHDL also induced endothelial nitric oxide synthase eNOS S1177 phosphorylation in HMEC-1 but only when the particle contained sphingomyelin. In conclusion, the internalization of HDL implies the dissociation of lipoprotein components and a SR-BI-independent fast delivery of cholesterol to endothelial cells. HDL internalization had functional implications that were mainly dependent on sphingomyelin. These results suggest a new role of HDL as lipid vectors to the cells, which could be congruent with the antiatherogenic properties of these lipoproteins.