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.

M. High-sucrose diet increases ROS generation, FFA accumulation, UCP2 level, and proton leak in liver mitochondria. Am J Physiol Endocrinol Metab 301: E1198 -E1207, 2011. First published September 13, 2011 doi:10.1152/ajpendo.00631.2010.-Obesity, a risk factor for insulin resistance, contributes to the development of type 2 diabetes and cardiovascular diseases. The relationship between increased levels of free fatty acids in the liver mitochondria, mitochondrial function, and ROS generation in rat model of obesity induced by a high-sucrose diet was not sufficiently established. We determined how the bioenergetic functions and ROS generation of the mitochondria respond to a hyperlipidemic environment. Mitochondria from sucrose-fed rats generated H2O2 at a higher rate than the control mitochondria. Adding fatty acid-free bovine serum albumin to mitochondria from sucrose-fed rats significantly reduced the rate of H2O2 generation. In contrast, adding exogenous oleic or linoleic acid exacerbated the rate of H2O2 generation in both sucrose-fed and control mitochondria, and the mitochondria from sucrose-fed rats were more sensitive than the control mitochondria. The increased rate of H2O2 generation in sucrose-fed mitochondria corresponded to decreased levels of reduced GSH and vitamin E and increased levels of Cu/Zn-SOD in the intermembrane space. There was no difference between the levels of lipid peroxidation and protein carbonylation in the two types of mitochondria. In addition to the normal activity of Mn-SOD, GPX and catalase detected an increased activity of complex II, and upregulation of UCP2 was observed in mitochondria from sucrose-fed rats, all of which may accelerate respiration rates and reduce generation of ROS. In turn, these effects may protect the mitochondria of sucrose-fed rats from oxidative stress and preserve their function and integrity. However, in whole liver these adaptive mechanisms of the mitochondria were inefficient at counteracting redox imbalances and inhibiting oxidative stress outside of the mitochondria. reactive oxygen species; free fatty acid; metabolic syndrome; mitochondrial function; oxidative stress; uncoupling protein 2 ABDOMINAL OBESITY AND HIGH LEVELS of circulating free fatty acids (FFAs) have been indicated as primary contributors to acquired insulin resistance and hypertension because they induce oxidative stress that affects insulin signaling and nitric oxide availability (30, 11). Insulin resistance leads to continuous lipolysis within adipocytes, releasing FFAs into the local circulation, where they are transported into the liver. In the liver, FFAs can be incorporated into triglycerides that accumulate and lead to nonalcoholic fatty liver disease, the primary hepatic complication of obesity (13, 57). Oxidative stress and mitochondrial dysfunction have been shown to play a critical role in the initiation and progression of fatty liver to the more serious condition of nonalcoholic steatohepatitis in obesity models (15,21,38). Several studies using an animal model of fa...

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.

Dehydroepiandrosterone (DHEA), a steroid hormone, modified the proliferation of human umbilical vein endothelial cells in a dose‐dependent manner. Its inactive sulfate ester (DHEA‐S) and two of its metabolites – estradiol and testosterone – had no inhibitory effect at physiological concentrations. Antiproliferation was associated with arrest in the G1 phase of the cell cycle, but not with cell death, as evaluated by cleavage of poly(ADP‐ribose) polymerase and exposure of phosphatidylserine. The effect was not blocked by inhibitors of androgen or estrogen receptors. DHEA diminished the levels of phosphorylated retinoblastoma protein and increased the expression of p53 and p21 mRNAs. These results show that DHEA inhibits endothelial cell proliferation by regulating cell cycle relevant proteins through a cytoplasmic steroid hormone‐independent pathway.

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