Increased transforming growth factor-beta1circulating levels and production in human monocytes after 3-hydroxy-3-methyl-glutaryl-coenzyme a reductase inhibition with pravastatin

AbstractObjectivesWe sought to determine whether inhibition of 3-hydroxy-3-methyl-glutaryl-coenzyme A (HMG-CoA) reductase with pravastatin affects transforming growth factor-beta1(TGF-beta1) circulating levels and its production in the monocytes of hypercholesterolemic patients.BackgroundTransforming growth factor-beta1is a multifunctional growth factor/cytokine involved in many physiologic and pathologic processes, such as vascular remodeling and atherogenesis. Statins have been reported to have a modulatory role in cytokine expression in the monocytes of hyperlipidemic patients.MethodsWe evaluated, in a cross-over study design, plasma TGF-beta1levels and ex vivo TGF-beta1production in the monocytes of hypercholesterolemic patients before and after four to six weeks of lipid-lowering treatment with diet or diet plus 40 mg/day of pravastatin. In addition, isolated blood monocytes were subjected to pravastatin treatment and evaluated for TGF-beta1messenger ribonucleic acid (mRNA) expression and TGF-beta1in vitro production.ResultsLipid-lowering treatment significantly decreased total cholesterol and low-density lipoprotein cholesterol plasma levels. Pravastatin, but not a low lipid diet, induced a significant increase in TGF-beta1plasma levels (from 1.7 ± 0.5 ng/ml to 3.1 ± 1.1 ng/ml, p < 0.001) and in ex vivo monocyte production (from 1.8 ± 0.8 ng/ml to 3.9 ± 1.0 ng/ml, p < 0.001). The increase in TGF-beta1levels was not related to the changes in the lipid profile observed with pravastatin. An increase of approximately twofold in TGF-beta1production and in mRNA expression was also observed after in vitro treatment of human monocytes with pravastatin (5 μM). Co-incubation with mevalonate reversed the in vitro effect of pravastatin.Conclusions3-Hydroxy-3-methyl-glutaryl-coenzyme A reductase inhibition with pravastatin increases TGF-beta1plasma levels, as well as monocyte production, in hypercholesterolemic patients. The mevalonate pathway plays a role in the regulation of TGF-beta1expression in human monocytes. A possible implication in the biologic and clinical effects of statins can be suggested

Inhibition of P-glycoprotein-mediated multidrug resistance by unfractionated heparin: a new potential chemosensitizer for cancer therapy.

Anticoagulant treatment with heparins is frequently used to prevent venous thromboembolism in cancer patients. In the present study, we investigated the ability of unfractionated heparin (UFH) to inhibit P-glycoprotein (Pgp)-mediated multidrug resistance (MDR) on human breast cancer cell line (MDA-MB231) and its doxo-resistant subline. Results were a compared to the classic reversing agent, Verapamil (Ver), used, as reference at 50 microM concentration. We analysed the Pgp function by calcein acetoxymethylester (calcein-AM) uptake, a fluorescent marker substrate, before and after in vitro exposure to UFH at clinically achievable dose of 20 U/ml. The mean percentage of calcein-AM retained into cancer cells after 3 and 12 h were 32 +/- 10.9 and 45 +/- 12.3, respectively, for UFH pretreated cells and 25.3 +/- 8.7 and 29.4 +/- 10.4, respectively, for Ver pretreated cells when compared to control cells, receiving only medium. Pgp activity was studied by measuring intracellular drug accumulation in doxo-resistant subline, treated (2 h) with either UFH or Ver, prior exposure (2 h) at different doxo concentrations (2, 4 and 8 microM). The mean percentage of remaining intracellular doxo were 55.4 +/- 4.5 , 51.4 +/- 3.9 and 50 +/- 1.8 percent, respectively for UFH treated cells, and 44.1 +/- 5.8, 39.3 +/- 4.4 and 19.4 +/- 8.6%, respectively, for Ver treated cells as compared with control cells, receiving only doxo. These results were consistent with the increase of sensitivity to doxo of the same doxo-resistant subline resulting in a 2.2, 2.6 and 2.2-fold increase, respectively, for UFH-doxo combination and 2.2, 2.5 and 2.0-fold respectively, for Ver-doxo combination respect to cells receiving doxo alone, as assessed by MTT test. In conclusion, these findings demonstrate the potentiating effect in vitro of UFH on doxo accumulation and cytotoxicity in the MDA-231 cell line and its doxo-resistant subline and suggest that UFH could to be used, as an potential chemosensitizer, in clinical chemotherapy for increasing in vivo, the efficacy of the anticancer treatment

Reduced variability to aspirin antiplatelet effect by the coadministration of statins in high-risk patients for cardiovascular disease

We studied the influence of cardiovascular(CV) risk factors, previous CV events, and co-treatments with preventive medicines, on residual platelet thromboxane(TX)B2production in 182 patients chronically treated with enteric coated(EC)-aspirin(100mg/day). The response to aspirin was also verified by assessing arachidonic acid-induced platelet aggregation and urinary 11-dehydro-TXB2levels. Residual serum TXB2levels exceeded the upper limit value for an adequate aspirin response in 14% of individuals. This phenomenon was detected at 12h after dosing with aspirin. The co-administration of statins(atorvastatin, used mostly) was an independent predictor of residual serum TXB2levels, and the percentage of patients with enhanced values was significantly lower in statin users vs. nonusers. We provide evidence in vitro that atorvastatin reduced residual TXB2generation by increasing the extent of acetylation of platelet COX-1 by aspirin. In conclusion, the coadministration of statins may counter the mechanisms associated with reduced bioavailability of aspirin detected in some individuals with CV disease. This article is protected by copyright. All rights reserved