(3S-5S-6E)-7-[3-(4-fluorophenyl)-1-(propan-2-yl)-1H-indol-2-yl]-3-5-dihydroxyhept-6-enoic-acid and Reperfusion-Injury

Fluvastatin, a traditional fat-decreasing drug, is widely used for curing cardiovascular disease. Previous reports demonstrated that fluvastatin pretreatment protected against myocardial ischemia/reperfusion (I/R) by inhibiting TLR4 signaling pathway and/or reducing proinflammatory cytokines. However, whether fluvastatin has a cardioprotective effect against apoptosis and autophagy remains unknown. This study aims to evaluate whether the cardioprotective role of fluvastatin in I/R is mediated by high-mobility group box 1 (HMGB1)/toll-like receptor 4 (TLR4) pathway via anti-apoptotic and anti-autophagic functions. Sprague-Dawley rats were anesthetized, artificially ventilated and subjected to 30 min of coronary occlusion, followed by 4 h of reperfusion. The animals were randomized into four groups: (i) Sham operation; (ii) I/R; (iii) I/R + low-dosage fluvastatin (10 mg/kg); and (iv) I/R + high-dosage fluvastatin (20 mg/kg). After reperfusion, the hemodynamic parameters, myocardial infarct size, structural alteration of myocardium, apoptosis index, pro-inflammatory cytokine production, Beclin-1, Light chain 3 (LC3), HMGB1, TLR4 and Nuclear factor kappa B (NF-κB) protein levels were measured and recorded. It was found that fluvastatin preconditioning improved left ventricular dysfunction, reduced HMGB1/TLR4/NF-κB expressions, and inhibited cardiomyocyte apoptosis, autophagy, and inflammation reaction. Moreover, treatment with fluvastatin ameliorated myocardial injury by reducing infarct size, causing less damage to cardiac structure, downregulating autophagy-related protein expression and releasing pro-inflammation mediators. Our findings indicate that fluvastatin exerts beneficial effects on cardiac ischemic damage, which may be associated with its anti-autophagic and anti-apoptotic functions via inhibition of HMGB1/TLR4-related pathway during I/R injury.

Topics: Animals; Apoptosis; Autophagy; Cardiotonic Agents; China; Fluvastatin; HMGB1 Protein; Male; Myocardial Infarction; Myocardial Ischemia; Myocardial Reperfusion Injury; Myocardium; Myocytes, Cardiac; NF-kappa B; Rats; Rats, Sprague-Dawley; Reperfusion Injury; Signal Transduction; Toll-Like Receptor 4; Tumor Necrosis Factor-alpha

Ischemia reperfusion injury in the early posttransplant period affects immediate graft function and late allograft dysfunction. Recently, we showed that pharmacologic preconditioning with a calcineurin inhibitor improved transplant outcomes in rat syngeneic kidney transplantation. There is also evidence that cellular cholesterol content increases after many types of renal injury.. In this study, we looked at the effect of cyclosporine (CsA) on the donor kidney free cholesterol (FC) content in this model. Donor rats were pretreated with one dose of CsA 10 mg/kg administered 24 h or 7 days before being subjected to 2 h cold ischemia and then transplanted.. Pharmacologic preconditioning with CsA significantly improved renal function and histology and increased donor kidney FC content. On the other hand, fluvastatin co-administration with CsA abrogated that beneficial effect in association with a decrease in donor kidney FC content.. CsA preconditioning leads to better outcomes in kidney transplantation and is associated with up-regulation of renal FC content. The latter may then contribute to acquired cytoresistance, possibly by stabilizing the plasma membrane. Thus, use of statins around the time of transplantation may need to be evaluated until further studies are conducted to determine the clinical relevance of this observation.

Topics: Animals; Anticholesteremic Agents; Cholesterol; Cyclosporine; Fatty Acids, Monounsaturated; Fluvastatin; Humans; Immunosuppressive Agents; Indoles; Kidney; Kidney Cortex; Kidney Transplantation; Male; Rats; Rats, Inbred F344; Reperfusion Injury; Time Factors; Transplantation Conditioning

Angiogenesis requires the mobilization of progenitor cells from the bone marrow and homing of progenitor cells to ischemic tissue. Statins facilitate the former, and the chemokine stromal cell-derived factor-1 (SDF-1) enhances the latter. Their combined influence on angiogenesis was studied in vivo in the ischemic hindlimb C57BL/6 mouse model. The ischemic to non-ischemic perfusion ratio increased from 0.29 +/- 0.02 immediately after femoral excision to 0.51 +/- 0.10 three weeks after the surgery in the mice treated with either fluvastatin or SDF-1 alone, which is significantly better than the control (0.38 +/- 0.05, p < .05, n = 6). The combined use of fluvastatin and SDF-1 further improved the reperfusion ratio (0.62 +/- 0.08, p < .05). More cell proliferation, less apoptosis, enhanced bone marrow-derived endothelial progenitor cell (EPC) incorporation and higher capillary density were observed in ischemic tissue treated with both statin and SDF-1. In vitro mono-treatment with either fluvastatin (100 nM) or SDF-1 (100 ng/ml) facilitated EPC proliferation and migration, inhibited EPC apoptosis, enhanced expression of matrix metalloproteinase-2 (MMP-2) and -9 (MMP-9), and increased Akt phosphorylation and nitric oxide production. These effects were significantly augmented by the two agents together and ablated by inhibitors of either Akt or nitric oxide synthase (NOS). In conclusion, statin and SDF-1 additively enhance progenitor cell migration and proliferation and down-regulate EPC apoptosis, resulting in improved reperfusion via activation of the Akt/NOS pathway and up-regulation of MMP-2 and MMP-9 expression.

Topics: Animals; Apoptosis; Capillaries; Cell Movement; Cell Proliferation; Chemokine CXCL12; Endothelial Cells; Fatty Acids, Monounsaturated; Fluvastatin; Hindlimb; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Indoles; Ischemia; Male; Matrix Metalloproteinase 2; Matrix Metalloproteinase 9; Mice; Mice, Inbred C57BL; Muscles; Neovascularization, Physiologic; NIH 3T3 Cells; Nitric Oxide; Phosphorylation; Proto-Oncogene Proteins c-akt; Reperfusion Injury; Stem Cells