cerivastatin and Ischemia

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

The effects of aging on angiogenesis (vascular sprouting) and vasculogenesis (endothelial precursor cell [EPC] incorporation into vessels) are not well known. We examined whether ischemia-induced angiogenesis/vasculogenesis is altered in klotho (kl) mutant mice, an animal model of typical aging.. After unilateral hindlimb ischemia, laser Doppler blood-flow (LDBF) analysis revealed a decreased ischemic-normal LDBF ratio in kl mice. Tissue capillary density was also suppressed in kl mice (+/+>+/kl>kl/kl). Aortic-ring culture assay showed impaired angiogenesis in kl/kl mice, accompanied by reduced endothelium-derived nitric oxide release. Moreover, the rate of transplanted homologous bone marrow cells incorporated into capillaries in ischemic tissues (vasculogenesis) was lower in kl/kl mice than in wild-type (+/+) mice, which was associated with a decrease in the number of c-Kit+CD31+ EPC-like mononuclear cells in bone marrow and in peripheral blood. Finally, the 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor cerivastatin restored the impaired neovascularization in kl/kl mice, accompanied by an increase in c-Kit+CD31+ cells in bone marrow and peripheral blood, and enhanced angiogenesis in the aortic-ring culture.. Angiogenesis and vasculogenesis are impaired in kl mutant mice, a model of typical aging. Moreover, the age-associated impairment of neovascularization might be a new target of statin therapy.

Topics: Aging, Premature; Animals; Aorta, Thoracic; Bone Marrow Transplantation; Collateral Circulation; Cyclic GMP; Glucuronidase; Hindlimb; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Ischemia; Klotho Proteins; Laser-Doppler Flowmetry; Membrane Proteins; Mice; Mice, Mutant Strains; Models, Animal; Muscle, Skeletal; Neovascularization, Pathologic; Nitrates; Nitric Oxide; Nitrites; Organ Culture Techniques; Pyridines; Ultrasonography

The aim of this study was to test the feasibility of cine magnetic resonance imaging (MRI) for assessment of the infarcted rat and mouse heart and to compare the results with established methods. These models have been proven to predict genesis and prevention of heart failure in patients. The value of cine MRI was tested in studies investigating interventions to change the course of the remodeling process. MRI was performed for determination of left ventricular (LV) volumes and mass, myocardial infarct (MI) size and cardiac output. LV wet weight was determined after MRI. Rats underwent conventional hemodynamic measurements for determination of cardiac output and LV volumes by electromagnetic flowmeter and pressure-volume curves. Infarct size was determined by histology. MRI-acquired MI-size (18.5+/-2%) was smaller than that found by histology (22.8+/-2.5%, p<0.05) with close correlation (r=0.97). There was agreement in LV mass between MRI and wet weight (r=0.97, p<0.05) and in the MRI- and flowmeter measurements of cardiac output (r=0.80, p<0.05). Volume by MRI differed from pressure-volume curves with good correlation (r=0.96, p<0.05). In a serial study of mice after coronary ligation, LV hypertrophy at 8 weeks was detected (Sham 105.1+/-7.9 mg, MI 144.4+/-11.7 mg, p<0.05). Left ventricles were enlarged in infarcted mice (end-diastolic volume, week 8: Sham 63.5+/-4 microl, MI 94.2 microl, p<0.05). In conclusion, cine MRI is a valuable diagnostic tool applicable to the rat and mouse model of MI. Being non-invasive and exact it offers new insights into the remodeling process after MI because serial measurements are possible. The technique was applied to study several interventions and proved its usefulness.

Topics: Animals; Cardiac Output; Disease Models, Animal; Heart Failure; Heart Ventricles; Humans; Ischemia; Magnetic Resonance Imaging, Cine; Mice; Myocardial Infarction; Myocardial Ischemia; Pyridines; Rats; Reproducibility of Results; Sensitivity and Specificity; Species Specificity; Statistics as Topic; Stroke Volume; Testosterone; Ventricular Dysfunction, Left; Ventricular Remodeling

Postischemic acute renal failure (ARF) is common and often fatal. Cellular mechanisms include cell adhesion, cell infiltration and generation of oxygen free radicals, and inflammatory cytokine production. Hydroxy-3-methylglutaryl coenzyme A reductase inhibitors ("statins") directly influence inflammatory mechanisms. The hypothesis that ischemia-induced ARF could be ameliorated with statin treatment was investigated and possible molecular mechanisms were analyzed in a uninephrectomized rat model. Male Sprague-Dawley rats were pretreated with cerivastatin (0.5 mg/kg) or vehicle for 3 d. Ischemic ARF was induced by left renal artery clipping for 45 min, while the right kidney was being removed. After 24 h of ARF, serum creatinine levels were increased 7.5-fold in vehicle-treated control animals with ARF, compared with sham-operated animals (P < 0.005). Statin treatment reduced the creatinine level elevation by 40% (P < 0.005). Simultaneously, ischemia-induced severe decreases in GFR were significantly ameliorated by statin treatment (sham operation, 0.95 +/- 0.09 ml/min, n = 13; ischemia without treatment, 0.06 +/- 0.02 ml/min, n = 9; ischemia with statin pretreatment, 0.21 +/- 0.03 ml/min, n = 11; P < 0.001). Furthermore, statin pretreatment prevented the occurrence of tubular necrosis, with marked loss of the brush border, tubular epithelial cell detachment, and tubular obstruction in the S3 segment of the outer medullary stripe. In addition, monocyte and macrophage infiltration was almost completely prevented, intercellular adhesion molecule-1 upregulation was greatly decreased, and inducible nitric oxide synthase expression was reduced. Fibronectin and collagen IV expression was reduced, approaching levels observed in sham-operated animals. In vehicle-treated rats with ARF, mitogen-activated protein kinase extracellular activated kinase-1/2 activity was increased and the transcription factors nuclear factor-kappaB and activator protein-1 were activated. Statin treatment reduced this activation toward levels observed in sham-operated rats. The data suggest that hydroxy-3-methylglutaryl coenzyme A reductase inhibition protects renal tissue from the effects of ischemia-reperfusion injury and thus reduces the severity of ARF. The chain of events may involve anti-inflammatory effects, with inhibition of mitogen-activated protein kinase activation and the redox-sensitive transcription factors nuclear factor-kappaB and activator protein-1.

Topics: Acute Kidney Injury; Animals; Disease Models, Animal; Fibronectins; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Intercellular Adhesion Molecule-1; Ischemia; Kidney Glomerulus; Male; Mitogen-Activated Protein Kinase 1; Mitogen-Activated Protein Kinase 3; Mitogen-Activated Protein Kinases; NF-kappa B; Nitric Oxide Synthase; Nitric Oxide Synthase Type II; Pyridines; Rats; Rats, Sprague-Dawley

HMG-CoA (3-hydroxy-3-methylglutaryl-coenzyme A) reductase inhibitors, or statins, are prescribed widely to lower cholesterol. Accumulating evidence indicates that statins have various effects on vascular cells, which are independent of their lipid-lowering effect. Here, we tested the hypothesis that statins may augment collateral flow to ischemic tissues. We induced hind-limb ischemia in wild-type mice and treated them with either saline or cerivastatin. Cerivastatin enhanced the blood flow recovery dramatically as determined by Laser Doppler imaging. The mice treated with saline displayed frequent autoamputation of the ischemic toe, which was prevented completely by cerivastatin. Anti-CD31 immunostaining revealed that cerivastatin significantly increased the capillary density. Endothelial nitric oxide synthase (eNOS) activity was enhanced markedly in the mice treated with cerivastatin. The angiogenic effect of cerivastatin was abrogated in eNOS deficient (eNOS-/-) mice. These results indicate that eNOS is essential for cerivastatin to promote collateral growth in response to ischemia.

Topics: Animals; Capillaries; Collateral Circulation; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Ischemia; Laser-Doppler Flowmetry; Mice; Mice, Inbred C3H; Mice, Inbred C57BL; Mice, Knockout; Nitric Oxide Synthase; Nitric Oxide Synthase Type II; Nitric Oxide Synthase Type III; Pyridines; Regional Blood Flow; Vasodilation