pitavastatin and Ischemia

The TRUTH trial demonstrated that 8-month statin therapy alters the composition of coronary artery plaque using virtual histology (VH)-intravascular ultrasound (IVUS). The extended TRUTH study was conducted to evaluate the relationship between changes in coronary atherosclerosis and mid-term clinical outcomes and identify the factors associated with cardiovascular events.. Of 164 patients with angina pectoris who participated in the TRUTH trial, 119 subjects with analyzable IVUS data at both enrollment and the 8-month follow-up were enrolled and observed for at least two years. The primary end point was the time to first occurrence of cardiovascular composite events, including cardiovascular death, nonfatal myocardial infarction, nonfatal cerebral infarction, unstable angina and ischemic-driven revascularization, except for target lesion revascularization.. The frequency of reaching the primary end point was 13% (16/119), with a mean follow-up period of 41.9±9.4 months. Although plaque regression and changes in plaque composition were not associated with future cardiovascular events, the serum high-sensitivity C-reactive protein (hs-CRP) levels at the start of the extended TRUTH study were significantly higher in the event group than in the event-free group (1.43 mg/L vs. 0.58 mg/L, p=0.01). A multivariate logistic regression analysis showed that the hs-CRP level was an independent significant predictor of cardiovascular events (odds ratio: 1.69; 95% confidence interval: 1.14-2.50, p=0.01).. Coronary artery plaque regression and changes in plaque composition during statin therapy do not predict future cardiovascular events in patients with angina pectoris. Instead, the serum hs-CRP level can be used as a predictor of cardiovascular events.

Topics: Aged; Angina Pectoris; C-Reactive Protein; Cardiovascular Diseases; Coronary Artery Disease; Female; Follow-Up Studies; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Ischemia; Japan; Male; Middle Aged; Myocardial Infarction; Plaque, Atherosclerotic; Pravastatin; Prospective Studies; Quinolines; Regression Analysis; Risk Factors; Treatment Outcome; Ultrasonography, Interventional

Collaterals lessen tissue injury in occlusive disease. However, aging causes progressive decline in their number and smaller diameters in those that remain (collateral rarefaction), beginning at 16 months of age in mice (i.e., middle age), and worse ischemic injury-effects that are accelerated in even 3-month-old eNOS(-/-) mice. These findings have found indirect support in recent human studies.. We sought to determine whether other cardiovascular risk factors (CVRFs) associated with endothelial dysfunction cause collateral rarefaction, investigate possible mechanisms, and test strategies for prevention.. Mice with nine different models of CVRFs of 4-12 months of age were assessed for number and diameter of native collaterals in skeletal muscle and brain and for collateral-dependent perfusion and ischemic injury after arterial occlusion. Hypertension caused collateral rarefaction whose severity increased with duration and level of hypertension, accompanied by greater hindlimb ischemia and cerebral infarct volume. Chronic treatment of wild-type mice with L-N (G)-nitro-arginine methylester caused similar rarefaction and worse ischemic injury which were not prevented by lowering arterial pressure with hydralazine. Metabolic syndrome, hypercholesterolemia, diabetes mellitus, and obesity also caused collateral rarefaction. Neither chronic statin treatment nor exercise training lessened hypertension-induced rarefaction.. Chronic CVRF presence caused collateral rarefaction and worse ischemic injury, even at relatively young ages. Rarefaction was associated with increased proliferation rate of collateral endothelial cells, effects that may promote accelerated endothelial cell senescence.

Topics: Animals; Cardiovascular Diseases; Cell Proliferation; Collateral Circulation; Female; Hindlimb; Immunohistochemistry; Ischemia; Male; Mice; Mice, Inbred C57BL; Mice, Transgenic; Neovascularization, Pathologic; NG-Nitroarginine Methyl Ester; Nitric Oxide Synthase Type III; Physical Conditioning, Animal; Quinolines; Renin; Risk Factors; Time Factors

Notch signaling is reported to regulate angiogenesis, interacting with vascular endothelial growth factor (VEGF) signaling. HMG CoA reductase inhibitors (statins) also alter Notch signaling in vascular cells, but the mechanism and involvement of Notch and VEGF signaling in statin-mediated angiogenesis remain unclear. Here, we examined how statins activate the endothelial Notch1, and promote angiogenesis and arteriogenesis. We examined blood flow recovery after hindlimb ischemia in wild-type (WT) and Notch1 mutant mice treated with or without pitavastatin (3 mg/kg/day, p.o.). Although VEGF induction was not altered in ischemic limbs, pitavastatin promoted blood flow recovery in ischemic limbs in control mice but not in Notch1 mutant mice. Furthermore, pitavastatin induced endothelial ephrinB2 downstream of Notch1 and increased the density of both capillaries and arterioles in the ischemic limbs of WT but not of Notch1 mutant mice. Pitavastatin (100 nmol/l) rapidly activated γ-secretase and Notch1 in human umbilical vein endothelial cells without VEGF induction, which was suppressed by pharmacological inhibition and knockdown of Akt. Pitavastatin also augmented endothelial proliferation and tube formation on Matrigel, which were suppressed by either γ-secretase inhibition or knockdown of Notch1. Pitavastatin-induced microvascular sprouting was also impaired in Notch1 mutant aortic explants. Taken together, pitavastatin activates Notch1 through Akt-dependent stimulation of γ-secretase in endothelial cells, and thereby increases vasculogenesis without VEGF induction.

Topics: Animals; Arteries; Blood Circulation; Blotting, Western; Cell Line; Disease Models, Animal; Hindlimb; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Immunohistochemistry; Ischemia; Mice; Mice, Inbred C57BL; Neovascularization, Pathologic; Quinolines; Receptor, Notch1; Signal Transduction; Vascular Endothelial Growth Factor A

We recently demonstrated in a murine model that nanoparticle-mediated delivery of pitavastatin into vascular endothelial cells effectively increased therapeutic neovascularization. For the development of a clinically applicable approach, further investigations are necessary to assess whether this novel system can induce the development of collateral arteries (arteriogenesis) in a chronic ischemia setting in larger animals.. Chronic hind limb ischemia was induced in rabbits. They were administered single injections of nanoparticles loaded with pitavastatin (0.05, 0.15, and 0.5 mg/kg) into ischemic muscle.. Treatment with pitavastatin nanoparticles (0.5 mg/kg), but not other nanoparticles, induced angiographically visible arteriogenesis. The effects of intramuscular injections of phosphate-buffered saline, fluorescein isothiocyanate (FITC)-loaded nanoparticles, pitavastatin (0.5 mg/kg), or pitavastatin (0.5 mg/kg) nanoparticles were examined. FITC nanoparticles were detected mainly in endothelial cells of the ischemic muscles for up to 4 weeks. Treatment with pitavastatin nanoparticles, but not other treatments, induced therapeutic arteriogenesis and ameliorated exercise-induced ischemia, suggesting the development of functional collateral arteries. Pretreatment with nanoparticles loaded with vatalanib, a vascular endothelial growth factor receptor (VEGF) tyrosine kinase inhibitor, abrogated the therapeutic effects of pitavastatin nanoparticles. Separate experiments with mice deficient for VEGF receptor tyrosine kinase demonstrated a crucial role of VEGF receptor signals in the therapeutic angiogenic effects.. The nanotechnology platform assessed in this study (nanoparticle-mediated endothelial cell-selective delivery of pitavastatin) may be developed as a clinically feasible and promising strategy for therapeutic arteriogenesis in patients.

Topics: Angiogenesis Inducing Agents; Angiogenesis Inhibitors; Animals; Cells, Cultured; Chronic Disease; Collateral Circulation; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Carriers; Electric Stimulation; Endothelial Cells; Feasibility Studies; Hindlimb Suspension; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Injections, Intramuscular; Ischemia; Male; Mice; Mice, Knockout; Mice, Transgenic; Muscle, Skeletal; Nanoparticles; Neovascularization, Physiologic; Oxygen; Phthalazines; Protein Kinase Inhibitors; Pyridines; Quinolines; Rabbits; Regional Blood Flow; Time Factors; Vascular Endothelial Growth Factor Receptor-1

Recent clinical studies of therapeutic neovascularization using angiogenic growth factors demonstrated smaller therapeutic effects than those reported in animal experiments. We hypothesized that nanoparticle (NP)-mediated cell-selective delivery of statins to vascular endothelium would more effectively and integratively induce therapeutic neovascularization.. In a murine hindlimb ischemia model, intramuscular injection of biodegradable polymeric NP resulted in cell-selective delivery of NP into the capillary and arteriolar endothelium of ischemic muscles for up to 2 weeks postinjection. NP-mediated statin delivery significantly enhanced recovery of blood perfusion to the ischemic limb, increased angiogenesis and arteriogenesis, and promoted expression of the protein kinase Akt, endothelial nitric oxide synthase (eNOS), and angiogenic growth factors. These effects were blocked in mice administered a nitric oxide synthase inhibitor, or in eNOS-deficient mice.. NP-mediated cell-selective statin delivery may be a more effective and integrative strategy for therapeutic neovascularization in patients with severe organ ischemia.

Topics: Angiogenesis Inducing Agents; Angiogenic Proteins; Animals; Cells, Cultured; Disease Models, Animal; Drug Carriers; Endothelium, Vascular; Enzyme Inhibitors; Hindlimb; Humans; Injections, Intramuscular; Ischemia; Lactic Acid; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Muscle, Skeletal; Nanoparticles; Neovascularization, Physiologic; Nitric Oxide Synthase Type III; Polyglycolic Acid; Polylactic Acid-Polyglycolic Acid Copolymer; Proto-Oncogene Proteins c-akt; Quinolines; Regional Blood Flow; Time Factors

3-Hydroxy-3-methyl-glutaryl CoA reductase inhibitors, or statins, have pleiotropic effects and can protect the vasculature in a manner independent of their lipid-lowering effect. The effectiveness of statins in reducing the risk of coronary events has been shown even in patients with diabetes, and their effects on diabetic complications have been reported. Using a model of severe hindlimb ischemia in streptozotocin-induced diabetic mice (STZ-DM), we investigated the effects and mechanisms of statin therapy in diabetic angiopathy in ischemic hindlimbs. As a result, STZ-DM mice frequently lost their hindlimbs after induced ischemia, whereas non-DM mice did not. Supplementation with statins significantly prevented autoamputation. We previously showed that diabetic vascular complications are caused by impaired expression of PDGF-BB, but statin therapy did not enhance PDGF-BB expression. Statins helped enhance endogenous endothelial nitric oxide (NO) synthase (eNOS) expression. Furthermore, the inhibition of NO synthesis by the administration of N(omega)-nitro-l-arginine methyl ester impaired the ability of statins to prevent STZ-DM mouse limb autoamputation, indicating that the therapeutic effect of statins in hindlimb ischemia in STZ-DM mice occurs via the eNOS/NO pathway. A combination therapy of statins and PDGF-BB gene supplementation was more effective for diabetic angiopathy than either therapy alone. In conclusion, these findings indicate that statin therapy might be useful for preventing intractable diabetic foot disease in patients with diabetic angiopathy.

Topics: Animals; Becaplermin; Blood Glucose; Cells, Cultured; Cholesterol, LDL; Combined Modality Therapy; Diabetes Mellitus, Experimental; Diabetic Angiopathies; Diabetic Foot; Enzyme Inhibitors; Genetic Therapy; Glycation End Products, Advanced; Hindlimb; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Ischemia; Male; Mice; Mice, Inbred C57BL; Mice, Obese; Muscle, Skeletal; NG-Nitroarginine Methyl Ester; Nitric Oxide; Nitric Oxide Synthase Type II; Nitric Oxide Synthase Type III; Platelet-Derived Growth Factor; Pravastatin; Proto-Oncogene Proteins c-sis; Quinolines; Regional Blood Flow; Signal Transduction; Time Factors; Up-Regulation

To discuss the effect of Pitavastatin on angiogenesis in vivo and its mechanism in Klotho heterozygous deficient mice.. The heterozygous deficient Klotho mice (kl +/-) and wild mice (kl +/+) from the same litter were used to establish the animal model of hind-limb ischemia and grouped into control and Pitavastatin group, respectively. Hind-limb blood flow was evaluated using Laser Doppler perfusion imager (LDPI) before treatment and after operation of hind-limbs. The capillaries in muscle of limbs were counted by means of CD-31 labeled immuno-fluorescence. The phosphorylation of Akt (Protein kinase B) in cells was measured by direct immunohistochemical technique. The expression of vascular endothelial growth factors (VEGFs) in muscle of limbs was assessed using Western blotting.. After treatment of Pitavastatin, the blood flow in ischemic limbs of the Kl +/- and wild mice improved obviously, the ratio of blood flow area in ischemic limb to that in non-ischemic limb increased and the density of capillaries increased in ischemic limbs of the Kl +/- and wild mice. Pitavastatin enhanced the phosphorylation of Akt and the expression of VEGF in ischemic limbs of the Kl +/- and wild mice.. Pitavastatin has the pro-angiogenesis effect in vivo and the VEGF-p-Akt-NO pathway may be involved in the mechanism of the effect of Pitavastatin.

Topics: Angiogenesis Inducing Agents; Animals; Heterozygote; Ischemia; Male; Mice; Mice, Knockout; Quinolines; Vascular Endothelial Growth Factor A

We investigated the effects of pitavastatin on angiogenesis and perfusion in C3H/He mice with unilateral hind limb ischemia.. C3H/He mice treated with saline (n = 15) or pitavastatin (1 mg.kg(-1).d(-1), n = 15) per gavage for 1 week underwent unilateral hind limb ischemia surgery and were treated for another 5 weeks. Hind-limb blood flow was measured by Laser Doppler perfusion imager (LDPI, ischemic/nonischemic limb, %) at baseline, immediately after ischemia and weekly thereafter for 5 weeks. Endpoints included local vessel counts by immunofluorescence, phospho-Akt positive cell counts by immunoenzyme histochemical technique, vascular endothelial growth factors (VEGFs) expression in ischemic limbs by Western blot and serum nitric oxide metabolite (NOx) by chrome dioxide Griess method.. Lower extremity perfusion was significantly improved in pitavastatin treated mice vs. controls as measured by LDPI% at 1 week post ischemia and thereafter (P < 0.05). Pitavastatin treatment was associated with significantly increased capillary count [(47 +/- 11) vs. (26 +/- 14)/per high-power field (x 200), P < 0.05] and greater percentage of phospho-Akt positive cells [(6 +/- 1) vs. (2 +/- 0)/per high-power field (x 200), P < 0.05] in ischemic limbs. Serum NOx [(77.3 +/- 21.8) vs. (52.1 +/- 11.2) mol/L, P < 0.05) and VEGF protein expression in ischemic limbs were also significantly increased in pitavastatin group than those in control group.. Pitavastatin enhances angiogenesis and perfusion in CsH/He mice with limb ischemia.

Topics: Animals; Disease Models, Animal; Ischemia; Lower Extremity; Male; Mice; Mice, Inbred C3H; Neovascularization, Physiologic; Nitric Oxide; Quinolines; Vascular Endothelial Growth Factors

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