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

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

We have reported that chronically administered pravastatin prevented coronary artery reperfusion-induced lethal ventricular fibrillation (VF) in anesthetized rats without lowering the serum cholesterol level. The present study was undertaken to evaluate whether pravastatin prevents ischemia-induced lethal VF, simultaneously examining myeloperoxidase (MPO) activity in ischemic myocardial tissues. Anesthetized rats were subjected to 30-min ischemia and 60-min reperfusion after chronic administration of pravastatin (0.02, 0.2, and 2 mg/kg), fluvastatin (2 and 4 mg/kg), or vehicle for 22 days, orally, once daily. ECG and blood pressure were continually recorded, and MPO was measured by a spectrophotometer. Pravastatin and fluvastatin significantly (P<0.05) decreased MPO activities, but only pravastatin decreased the incidence of ischemia-induced lethal VF. Both statins had no significant effects on body weight, blood pressure, heart rate, and QT interval as we reported earlier. Our results prove further that pravastatin has benefits to decrease cardiovascular mortality beyond its cholesterol-lowering effect. Pravastatin is more potent than fluvastatin in prevention of arrhythmias. A decrease in the neutrophil infiltration may be partly involved in the inhibitory effect of pravastatin on the ischemia-induced VF.

Topics: Administration, Oral; Anesthesia; Animals; Arrhythmias, Cardiac; Coronary Vessels; Dose-Response Relationship, Drug; Drug Administration Schedule; Fatty Acids, Monounsaturated; Fluvastatin; Hydroxymethylglutaryl CoA Reductases; Indoles; Ischemia; Male; Peroxidase; Pravastatin; Rats; Rats, Sprague-Dawley

Recent clinical evidences indicate that statins may have beneficial effects on the functional recovery after ischemic stroke. However, the effect of delayed postischemic treatment with statins is still unclear. In the present study, we evaluated the effects of fluvastatin in the chronic stage of cerebral infarction in a rat model.. Rats exposed to permanent middle cerebral artery occlusion were treated for 3 months with fluvastatin beginning from 7 days after stroke. MRI, behavioral analysis, and immunohistochemistry were performed.. Two months of treatment with fluvastatin showed the significant recovery in spatial learning without the decrease in serum total cholesterol level and worsening of infarction. Microangiography showed a significant increase in capillary density in the peri-infarct region in fluvastatin-treated rats after 3 months of treatment. Consistently, BrdU/CD31-positive cells were significantly increased in fluvastatin-treated rats after 7 days of treatment. MAP1B-positive neurites were also increased in the peri-infarct region in fluvastatin-treated rats. In addition, rats treated with fluvastatin showed the reduction of superoxide anion after 7 days of treatment and the reduction of A beta deposits in the thalamic nuclei after 3 months of treatment.. Thus, delayed postischemic administration of fluvastatin had beneficial effects on the recovery of cognitive function without affecting the infarction size after ischemic stroke. Pleiotropic effects of fluvastatin, such as angiogenesis, neuritogenesis, and inhibition of superoxide production and A beta deposition, might be associated with a favorable outcome.

Topics: Animals; Anticholesteremic Agents; Cognition; Disease Models, Animal; Fatty Acids, Monounsaturated; Fluvastatin; Humans; Immunohistochemistry; Indoles; Infarction, Middle Cerebral Artery; Ischemia; Magnetic Resonance Imaging; Neovascularization, Pathologic; Rats; Rats, Wistar; Stroke; Superoxides; Treatment Outcome

3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors, or statins, are widely prescribed to lower cholesterol. Recent reports suggest that statins may promote angiogenesis in ischemic tissues. It remains to be elucidated whether statins potentially enhance unfavorable angiogenesis associated with tumor and atherosclerosis. Here, we induced hind limb ischemia in wild-type mice by resecting the right femoral artery and subsequently inoculated cancer cells in the same animal. Cerivastatin enhanced blood flow recovery in the ischemic hind limb as determined by laser Doppler imaging, whereas tumor growth was significantly retarded. Cerivastatin did not affect capillary density in tumors. Cerivastatin, pitavastatin, and fluvastatin inhibited atherosclerotic lesion progression in apolipoprotein E-deficient mice, whereas they augmented blood flow recovery and capillary formation in ischemic hind limb. Low-dose statins were more effective than high-dose statins in both augmentation of collateral flow recovery and inhibition of atherosclerosis. These results suggest that statins may not promote the development of cancer and atherosclerosis at the doses that augment collateral flow growth in ischemic tissues.

Topics: Animals; Apolipoproteins E; Arteriosclerosis; Fatty Acids, Monounsaturated; Femoral Artery; Fluvastatin; Hindlimb; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hypercholesterolemia; Indoles; Ischemia; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Neovascularization, Pathologic; Neovascularization, Physiologic; Nitric Oxide Synthase; Nitric Oxide Synthase Type II; Nitric Oxide Synthase Type III; Pyridines; Quinolines