|
1
|
Rizwan M, Faateh M, Dakour-Aridi H, Nejim B, Alshwaily W, Malas MB. Statins reduce mortality and failure to rescue after carotid artery stenting. J Vasc Surg 2019; 69:112-119. [DOI: 10.1016/j.jvs.2018.03.424] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/23/2017] [Accepted: 03/08/2018] [Indexed: 11/15/2022]
|
|
2
|
Affiliation(s)
| | - Mark A Creager
- Brigham and Women's Hospital, Harvard Medical School, USA
| |
Collapse
|
|
3
|
Antioxidant and anti-inflammatory effects of flavocoxid in high-cholesterol-fed rabbits. Naunyn Schmiedebergs Arch Pharmacol 2015; 388:1333-44. [DOI: 10.1007/s00210-015-1168-4] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2015] [Accepted: 08/16/2015] [Indexed: 02/06/2023]
|
|
4
|
El-Sheakh AR, Ghoneim HA, Suddek GM, Ammar ESM. Attenuation of oxidative stress, inflammation, and endothelial dysfunction in hypercholesterolemic rabbits by allicin. Can J Physiol Pharmacol 2015; 94:216-224. [PMID: 26618400 DOI: 10.1139/cjpp-2015-0267] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
Allicin, the active substance of garlic, exerts a broad spectrum of pharmacological activities and is considered to have potential therapeutic applications. The present study was designed to investigate the possible beneficial effects of allicin against oxidative stress, inflammation, and endothelial dysfunction in hypercholesterolemic rabbits. Male New Zealand white rabbits were used in this study. Rabbits randomly received 1 of the following treatments: normal chow diet for 4 weeks, 1% high cholesterol diet (HCD), HCD plus allicin (10 mg/kg/day), or HCD plus atorvastatin (10 mg/kg/day). Blood samples were collected at the end of experimental diets for measurement of serum total cholesterol (TC), triglycerides (TGs), high-density lipoprotein cholesterol (HDL-C), C-reactive protein (CRP), malondialdehyde (MDA), reduced glutathione (GSH), and superoxide dismutase (SOD). In addition, the aorta was removed for measurement of vascular reactivity, histopathological changes, intima/media (I/M) ratio, and immunohistochemical staining of both tumor necrosis-alpha (TNF-α) and nuclear factor (NF)-κB. HCD induced significant increases in serum TC, TGs, low-density lipoprotein cholesterol (LDL-C), CRP, and MDA. Moreover, HCD caused significant decrease in serum GSH and SOD. In addition, aortic relaxation response to acetylcholine (ACh) was impaired. Immunohistochemical staining of aortic specimens from HCD-fed rabbits revealed high expression levels of both TNF-α and the oxidant-induced transcription factor, NF-κB. Allicin supplementation significantly decreased serum MDA and CRP, increased serum HDL-C, GSH, and SOD levels while nonsignificantly affecting HCD-induced elevations in serum TC and LDL-C. Additionally, allicin significantly protected against HCD-induced attenuation of rabbit aortic endothelium-dependent relaxation to ACh and elevation in I/M ratio. This effect was confirmed by histopathological examination of the aorta. Moreover, allicin has substantially beneficial effects on aortic expression of TNF-α and NF-κB compared with HCD-fed rabbits. In conclusion, these findings demonstrate that allicin may be useful in reducing oxidative stress, inflammation, vascular dysfunction, and the aortic pathology in hypercholesterolemic rabbits.
Collapse
Affiliation(s)
- Ahmed R El-Sheakh
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Mansoura University, Mansoura 35516, Egypt.,Department of Pharmacology and Toxicology, Faculty of Pharmacy, Mansoura University, Mansoura 35516, Egypt
| | - Hamdy A Ghoneim
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Mansoura University, Mansoura 35516, Egypt.,Department of Pharmacology and Toxicology, Faculty of Pharmacy, Mansoura University, Mansoura 35516, Egypt
| | - Ghada M Suddek
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Mansoura University, Mansoura 35516, Egypt.,Department of Pharmacology and Toxicology, Faculty of Pharmacy, Mansoura University, Mansoura 35516, Egypt
| | - El Sayed M Ammar
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Mansoura University, Mansoura 35516, Egypt.,Department of Pharmacology and Toxicology, Faculty of Pharmacy, Mansoura University, Mansoura 35516, Egypt
| |
Collapse
|
|
5
|
Pecoraro V, Moja L, Dall'Olmo L, Cappellini G, Garattini S. Most appropriate animal models to study the efficacy of statins: a systematic review. Eur J Clin Invest 2014; 44:848-71. [PMID: 25066257 DOI: 10.1111/eci.12304] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/19/2013] [Accepted: 07/21/2014] [Indexed: 12/21/2022]
Abstract
BACKGROUND In animal models and clinical trials, statins are reported as effective in reducing cholesterol levels and lowering the risk of cardiovascular diseases. We have aggregated the findings in animal models - mice, rats and rabbits - using the technique of systematic review and meta-analysis to highlight differences in the efficacy of statins. MATERIALS AND METHODS We searched Medline and Embase. After examining all eligible articles, we extracted results about total cholesterol and other blood parameters, blood pressure, myocardial infarction and survival. Weighted and standard mean difference random effects meta-analysis was used to measure overall efficacy in prespecified species, strains and subgroups. RESULTS We included in systematic review 161 animal studies and we analysed 120 studies, accounting for 2432 animals. Statins lowered the total cholesterol across all species, although with large differences in the effect size: -30% in rabbits, -20% in mice and -10% in rats. The reduction was larger in animals fed on a high-cholesterol diet. Statins reduced infarct volume but did not consistently reduce the blood pressure or effect the overall survival. Few studies considered strains at high risk of cardiovascular diseases or hard outcomes. CONCLUSIONS Although statins showed substantial efficacy in animal models, few preclinical data considered conditions mimicking human pathologies for which the drugs are clinically indicated and utilized. The empirical finding that statins are more effective in lowering cholesterol derived from an external source (i.e. diet) conflicts with statin's supposed primary mechanism of action.
Collapse
Affiliation(s)
- Valentina Pecoraro
- Clinical Epidemiology Unit, IRCCS Orthopedic Institute Galeazzi, Milan, Italy
| | | | | | | | | |
Collapse
|
|
6
|
El-Awady MS, Suddek GM. Agmatine ameliorates atherosclerosis progression and endothelial dysfunction in high cholesterol-fed rabbits. J Pharm Pharmacol 2014; 66:835-43. [PMID: 24393128 DOI: 10.1111/jphp.12204] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2013] [Accepted: 11/30/2013] [Indexed: 12/27/2022]
Abstract
OBJECTIVES The aim of this work was to explore possible effects of agmatine, an endogenous inhibitor of inducible nitric oxide synthase (iNOS), against hypercholesterolemia-induced lipid profile changes and endothelial dysfunction. METHODS Hypercholesterolemia was induced by feeding rabbits with a high-cholesterol diet (HCD, 0.5%) for 8 weeks. Another HCD-fed group was orally administered agmatine (10 mg/kg/day) during weeks 5 through 8. Serum lipid profile, malondialdehyde (MDA), nitric oxide (NO) and lactate dehydrogenase (LDH) were determined. Aorta was isolated to analyse vascular reactivity, atherosclerotic lesions and intima/media (I/M) ratio. KEY FINDINGS HCD induced a significant increase in serum total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), triglycerides and high-density lipoprotein cholesterol (HDL-C). Agmatine administration significantly decreased HCD-induced elevations in serum TC and LDL-C, MDA, LDH and NO while significantly increased HDL-C levels. Additionally, agmatine significantly protected against HCD-induced attenuation of rabbit aortic endothelium-dependent relaxation to acetylcholine. HCD and agmatine did not significantly influence aortic endothelium-independent relaxation to sodium nitroprusside. Moreover, agmatine significantly reduced the elevation in aortic atherosclerotic lesion area and I/M ratio. CONCLUSIONS This study is the first to reveal that agmatine has the ability to ameliorate hypercholesterolemia-induced lipemic-oxidative and endothelial function injuries possibly by its antioxidant potential and/or iNOS inhibition.
Collapse
Affiliation(s)
- Mohammed S El-Awady
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Mansoura University, Mansoura, Egypt
| | | |
Collapse
|
|
7
|
|
|
8
|
Abstract
Atherosclerosis is a chronic inflammatory process in the intima of conduit arteries, which disturbs the endothelium-dependent regulation of the vascular tone by the labile liposoluble radical nitric oxide (NO) formed by the constitutive endothelial nitric oxide synthase (eNOS). This defect predisposes to coronary vasospasm and cardiac ischaemia, with anginal pain as the typical clinical manifestation. It is now appreciated that endothelial dysfunction is an early event in atherogenesis and that it may also involve the microcirculation, in which atherosclerotic lesions do not develop. On the other hand, the inflammatory environment in atherosclerotic plaques may result in the expression of the inducible NO synthase (iNOS) isozyme. Whether the dysfunction in endothelial NO production is causal to, or the result of, atherosclerotic lesion formation is still highly debated. Most evidence supports the hypothesis that constitutive endothelial NO release protects against atherogenesis e.g. by preventing smooth muscle cell proliferation and leukocyte adhesion. Nitric oxide generated by the inducible isozyme may be beneficial by replacing the failing endothelial production but excessive release may damage the vascular wall cells, especially in combination with reactive oxygen intermediates.
Collapse
Affiliation(s)
- K E Matthys
- University of Antwerp (UIA) Division of Pharmacology Wilrijk Antwerp B2610 Belgium
| | | |
Collapse
|
|
9
|
Kamal SM. Effects of single-dose morning and evening administration of pravastatin on antioxidant markers in cholesterol-fed rabbits. J Exp Pharmacol 2011; 3:51-8. [PMID: 27186110 PMCID: PMC4863309 DOI: 10.2147/jep.s19449] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/23/2022] Open
Abstract
BACKGROUND Accurate timing of statin administration is considered important to obtain the best hypolipidemic effect. Pravastatin is one of the currently prescribed hepatic 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors, and was chosen in this study to evaluate its antioxidant effect when administered as a single daily dose in the morning versus evening in cholesterol-fed rabbits. METHODS This 12-week study was performed in New Zealand rabbits, divided into four groups (n = 6 each), ie, normocholesterolemic controls; cholesterol 1% diet, nontreated ; cholesterol 1% diet treated with pravastatin in the morning; and cholesterol 1% diet treated with pravastatin in the evening. Plasma total cholesterol levels, superoxide dismutase enzyme levels in erythrocyte lysates, thiobarbituric acid-reactive substance content, catalase, and glutathione enzyme activity in liver homogenates from the tested rabbits were measured. RESULTS Both morning and evening treatment with pravastatin significantly improved all the measured antioxidant markers in comparison with nontreated cholesterol-fed rabbits. However, results obtained with evening dosing were better than with morning dosing. CONCLUSION The antioxidant profile of pravastatin is better when the drug is administered in the evening rather than in the morning.
Collapse
Affiliation(s)
- Sahar Mohamed Kamal
- Department of Pharmacology, Faculty of Medicine, Ain Shams University, Cairo, Egypt
| |
Collapse
|
|
10
|
Simvastatin in contrast to postconditioning reduces infarct size in hyperlipidemic rabbits: possible role of oxidative/nitrosative stress attenuation. Basic Res Cardiol 2010; 105:193-203. [DOI: 10.1007/s00395-009-0078-3] [Citation(s) in RCA: 58] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/07/2009] [Revised: 12/07/2009] [Accepted: 12/12/2009] [Indexed: 11/25/2022]
|
|
11
|
Osipov RM, Bianchi C, Feng J, Clements RT, Liu Y, Robich MP, Glazer HP, Sodha NR, Sellke FW. Effect of hypercholesterolemia on myocardial necrosis and apoptosis in the setting of ischemia-reperfusion. Circulation 2009; 120:S22-30. [PMID: 19752371 DOI: 10.1161/circulationaha.108.842724] [Citation(s) in RCA: 79] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/08/2023]
Abstract
BACKGROUND Hypercholesterolemia is prevalent in patients who experience myocardial ischemia-reperfusion injury (IR). We investigate the impact of dietary-induced hypercholesterolemia on the myocardium in the setting of acute IR. METHODS AND RESULTS In normocholesterolemic (NC, n=7) and hypercholesterolemic (HC, n=7) Yucatan male pigs, the left anterior descending coronary artery was occluded for 60 minutes, followed by reperfusion for 120 minutes. Hemodynamic values were recorded, and TTC staining was used to assess necrosis. Oxidative stress was measured. Specific cell death and survival signaling pathways were assessed by Western blot and TUNEL staining. Infarct size was 45% greater in HC versus NC (42% versus 61%, P<0.05), whereas the area at risk (AAR) was similar in both groups (P=0.61). Whereas global LV function (+dP/dt, P<0.05) was higher during entire period of IR in HC versus NC, regional function deteriorated more following reperfusion in HC (P<0.05). Ischemia increased indices of myocardial oxidative stress such as protein oxidation (P<0.05), lipid peroxidation (P<0.05), and nitrotyrosylation in HC versus NC, as well as the expression of phospho-eNOS (P<0.05). The expression of myeloperoxidase, p38 MAPK, and phospho-p38 MAPK was higher in HC versus NC (all P<05). Ischemia caused higher expression of the proapoptotic protein PARP (P<0.05), and lower expression of the prosurvival proteins Bcl2 (P<0.05), phospho-Akt, (P<0.05), and phospho-PKCepsilon (P<0.05) in the HC versus NC. TUNEL-positive cell count was 3.8-fold (P<0.05) higher in the AAR of HC versus NC. CONCLUSIONS This study demonstrates that experimental hypercholesterolemia is associated with increased myocardial oxidative stress and inflammation, attenuation of cell survival pathways, and induction of apoptosis in the ischemic territory, which together may account for the expansion of myocardial necrosis in the setting of acute IR.
Collapse
Affiliation(s)
- Robert M Osipov
- Alpert School of Medicine at Brown University, Rhode Island Hospital, Providence, 02905, USA
| | | | | | | | | | | | | | | | | |
Collapse
|
|
12
|
Affiliation(s)
- Harinath Chakrapani
- Department of Chemistry, Duke University, B 120 Levine Science Research Center, Durham, North Carolina 27708
| | - Michael D. Bartberger
- Department of Chemistry, Duke University, B 120 Levine Science Research Center, Durham, North Carolina 27708
| | - Eric J. Toone
- Department of Chemistry, Duke University, B 120 Levine Science Research Center, Durham, North Carolina 27708
| |
Collapse
|
|
13
|
Liu HR, Tao L, Gao E, Qu Y, Lau WB, Lopez BL, Christopher TA, Koch W, Yue TL, Ma XL. Rosiglitazone inhibits hypercholesterolaemia-induced myeloperoxidase upregulation--a novel mechanism for the cardioprotective effects of PPAR agonists. Cardiovasc Res 2008; 81:344-52. [PMID: 19010810 DOI: 10.1093/cvr/cvn308] [Citation(s) in RCA: 39] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/23/2023] Open
Abstract
AIMS Hypercholesterolaemia and myeloperoxidase (MPO) overexpression are two well-recognized risk factors for ischaemic heart disease. Peroxisome proliferator-activated receptor-gamma (PPARgamma) agonists have recently been shown to reduce ischaemic heart injury in hypercholesterolaemic animals. However, whether PPARgamma agonists may exert their cardioprotective effects by eliminating those risk factors that increase ischaemic injury remains unknown. METHODS AND RESULTS Male New Zealand rabbits were fed with a normal or a high-cholesterol diet for 8 weeks, treated with vehicle or rosiglitazone (RSG, 3 mg/kg/day for the last 5 weeks) and subjected to myocardial ischaemia/reperfusion (1 h/4 h). MPO expression, activity, and distribution, cardiac caspase-3 activity, and myocardial infarct size were determined. Diet-induced hypercholesterolaemia caused a significant increase in neutrophil MPO expression/activity (7.2-/5.4-fold). Hypercholesterolaemia also tripled MPO activity in ischaemic/reperfused hearts when compared with rabbits fed with a normal diet. Surprisingly, MPO immunostaining was not only observed in perivascular and extracellular spaces in ischaemic/reperfused hearts, but also in cardiomyocytes. This intracardiomyocyte MPO staining was further intensified by hypercholesterolaemia. There is a strong positive correlation between cardiac MPO activity and caspase-3 activity, and treatment with an MPO inhibitor significantly reduced post-ischaemic caspase-3 activation. Treatment with RSG markedly inhibited hypercholesterolaemia-induced leucocyte MPO overexpression and activation, reduced MPO activity in ischaemic/reperfused hearts, decreased caspase-3 activity, and reduced myocardial infarct size (P < 0.01). CONCLUSION Our results demonstrated that hypercholesterolaemia and MPO overexpression are causally related and that PPARgamma agonists may have great therapeutic value in ischaemic heart disease patients with multiple complications such as hypercholesterolaemia and diabetes.
Collapse
Affiliation(s)
- Hui-Rong Liu
- Department of Emergency Medicine, Thomas Jefferson University, 1020 Sansom Street, Thompson Building, Room 241, Philadelphia, PA 19107, USA
| | | | | | | | | | | | | | | | | | | |
Collapse
|
|
14
|
Alessi A, França Neto OR, Brofman PRS, Prim C, Noronha L, Silva RFKC, Baroncini LAV, Précoma DB. Use of rosiglitazone before and after vascular injury in hypercholesterolemic rabbits: Assessment of neointimal formation. Thromb J 2008; 6:12. [PMID: 18752684 PMCID: PMC2538502 DOI: 10.1186/1477-9560-6-12] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2008] [Accepted: 08/27/2008] [Indexed: 01/12/2023] Open
Abstract
Objectives To analyse the effects of rosiglitazone administered at different times on neointimal formation in hypercholesterolemic rabbits following vascular injury. Methods Thirty-nine rabbits on a hypercholesterolemic diet were included. The animals underwent balloon catheter injury to the right iliac artery on day 14. They were divided into three groups as follows: control group, 13 rabbits without rosiglitazone; group I, 13 rabbits treated with rosiglitazone (3 mg/Kg body weight/day) for 28 days after the vascular injury; and group II, 13 rabbits treated with rosiglitazone (3 mg/Kg body weight/day) during all the experiment (42 days). Histological analysis was done by an experienced pathologist who was unaware of the rosiglitazone treatment. Histomorphometric parameters were performed by calculation of the luminal and intimal layer area, and intima/media layer area ratio (the area of the intimal layer divided by the area of the medial layer). Results Intimal area was significantly lower in group II vs. CG (p = 0.024) and group I (p = 0.006). Luminal layer area was higher in group II vs. CG (p < 0.0001) and group I (p < 0.0001). Intima/media layer area ratio was equal between CG and group I. Intima/media layer ratio area was significantly lower in group II vs. control group (p < 0.021) and group I (p < 0.003). There was a significant reduction of 65% and 71% in intima/media layer area ratio in group II vs. control group and group I, respectively. Conclusion Pretreatment with rosiglitazone in hypercholesterolemic rabbits submitted to vascular injury significantly reduces neointimal formation.
Collapse
Affiliation(s)
- Alexandre Alessi
- Center of Health and Biological Sciences, Pontifical Catholic University of Paraná, Brazil.
| | | | | | | | | | | | | | | |
Collapse
|
|
15
|
Işeri S, Ercan F, Gedik N, Yüksel M, Alican I. Simvastatin attenuates cisplatin-induced kidney and liver damage in rats. Toxicology 2007; 230:256-64. [PMID: 17196726 DOI: 10.1016/j.tox.2006.11.073] [Citation(s) in RCA: 121] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2006] [Revised: 11/20/2006] [Accepted: 11/20/2006] [Indexed: 10/23/2022]
Abstract
Statins have anti-inflammatory effects that are not directly related to their cholesterol-lowering activity. This study aimed to investigate the effect of simvastatin on the extent of tissue damage in cisplatin-induced nephrotoxicity and hepatotoxicity. The rats received a single intravenous injection of 2.5mgkg(-1) cisplatin. Other groups received either simvastatin (1mgkg(-1)) or the vehicle (ethanol:saline) intraperitoneally for 10 days beginning 5 days prior to cisplatin injection. All animals were decapitated 5 days after cisplatin administration. Trunk blood was collected and analyzed for blood urea nitrogen (BUN), creatinine, alanine aminotransferase (ALT), aspartate aminotransferase (AST), lactate dehydrogenase (LDH), albumin, and total bilirubin levels. The urine samples were used for the calculation of creatinine clearance levels. The kidney and liver samples were stored for the measurement of malondialdehyde (MDA) and glutathione (GSH) levels, myeloperoxidase (MPO) activity and collagen content or were processed for histopathological examinations. Formation of reactive oxygen species in tissue samples was monitored by using chemiluminescence method. Simvastation reduced the extent of both kidney and liver damage and preserved both kidney and liver functions (p<0.01-0.001). Increase in liver MDA level with a concomitant reduction in GSH in the cisplatin group was attenuated by simvastatin treatment (p<0.05-0.01). Increase in tissue collagen content and chemiluminescence levels in the kidney and liver samples of the cisplatin group was also reversed by simvastatin (p<0.001). In conclusion, simvastatin is beneficial in cisplatin-induced kidney and liver dysfunction and organ damage in rats via prevention of lipid peroxidation and tissue fibrosis, preservation of antioxidant glutathione, and suppression of neutrophil infiltration.
Collapse
Affiliation(s)
- Sevgin Işeri
- Marmara University School of Medicine, Department of Physiology, Istanbul, Turkey
| | | | | | | | | |
Collapse
|
|
16
|
Jahovic N, Gedik N, Ercan F, Sirvanci S, Yüksel M, Sener G, Alican I. Effects of statins on experimental colitis in normocholesterolemic rats. Scand J Gastroenterol 2006; 41:954-62. [PMID: 16803694 DOI: 10.1080/00365520600554444] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
OBJECTIVE The results of previous studies suggest that statins have a direct anti-inflammatory effect that is not directly related to their cholesterol-lowering activity. The aim of this study was to investigate the effect of simvastatin (SIM) and fluvastatin (FLU) on trinitrobenzene sulfonic acid (TNBS)-induced colonic inflammation in rats. MATERIAL AND METHODS The drugs were given for 3 days (0.1 and 1 mg/kg day-1; intraperitoneally) after induction of colitis. The lesions in the distal colon were scored at the macroscopic and microscopic level. Tissue malondialdehyde (MDA) and glutathione (GSH) levels, myeloperoxidase (MPO) activity and collagen content were assessed and formation of reactive oxygen species and peroxynitrite was monitored by chemiluminescence (CL) assay. Trunk blood was collected for the measurement of serum tumor necrosis factor (TNF)-alpha level. RESULTS Treatment with SIM reduced the lesion score of the colitis group at macroscopic level (p<0.05), but there was no effect of treatment with FLU. The increase in colonic MDA level of the colitis group was reduced by both drugs at all doses (p<0.05-0.001). The decrease in GSH and the an increase in MPO activity in the colitis group were reversed by SIM at all doses (p<0.01), but FLU had no effect. An increase in colonic lucigenin CL value in the colitis group was reduced by SIM and FLU at all doses (p<0.001) and an increase in peroxynitrite ratio in the colitis group showed a significant reduction in SIM-treated groups; FLU reduced this effect at a dose of 1 mg/kg (p<0.01). An increase in tissue collagen content and serum TNF-alpha level in the colitis group was reversed by both drugs at all doses (p<0.001). CONCLUSIONS SIM and FLU seemed to be beneficial in a TNBS-induced rat colitis model through the prevention of lipid peroxidation, superoxide generation, cytokine production and neutrophil accumulation.
Collapse
Affiliation(s)
- Nermina Jahovic
- Department of Physiology, Marmara University School of Medicine, and Kasimpaşa Military Hospital, Divison of Biochemistry, Haydarpaşa, Istanbul, Turkey
| | | | | | | | | | | | | |
Collapse
|
|
17
|
Sen M, Anadol AZ, Oğuz M. Effect of hypercholesterolemia on experimental colonic anastomotic wound healing in rats. World J Gastroenterol 2006; 12:1225-8. [PMID: 16534875 PMCID: PMC4124433 DOI: 10.3748/wjg.v12.i8.1225] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To evaluate the mechanical and biochemical parameters of colonic anastomotic healing in hypercholesterolemic rats.
METHODS: Sixty rats were divided into two groups of 30 each according to their dietary regimens. The test group was fed with a high cholesterol-containing diet for two months while the control group had standard diet. These two groups were further divided into three subgroups consisting of ten rats each. After hypercholesterolemia was established, left colon resection and anastomosis were performed in both groups and samples from liver and abdominal aorta were taken to evaluate the systemic effects of hypercholesterolemia. Anastomotic wound healing, blow-out pressures and tissue hydroxyproline levels were evaluated.
RESULTS: The test group had a significant weight gain in two months. Microscopic examination of the abdominal aorta revealed no atherosclerotic change in none of the groups, but liver tissue specimens showed significant steatosis in the test group. Tissue hydroxyproline levels and anastomotic blow-out pressures were significantly lower in the test group than in the controls.
CONCLUSION: Hypercholesterolemia not only increases hydroxyproline levels and blow-out pressures but also worsens anastomotic wound healing.
Collapse
Affiliation(s)
- Meral Sen
- Department of Surgery, School of Medicine, Fatih University, 06500 Ankara, Turkey.
| | | | | |
Collapse
|
|
18
|
Fonarow GC, Wright RS, Spencer FA, Fredrick PD, Dong W, Every N, French WJ. Effect of statin use within the first 24 hours of admission for acute myocardial infarction on early morbidity and mortality. Am J Cardiol 2005; 96:611-6. [PMID: 16125480 DOI: 10.1016/j.amjcard.2005.04.029] [Citation(s) in RCA: 183] [Impact Index Per Article: 9.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/23/2005] [Revised: 04/21/2005] [Accepted: 04/21/2005] [Indexed: 01/26/2023]
Abstract
We determined the effects of early statin treatment in acute myocardial infarction (AMI) on in-hospital morbidity and mortality. Experimental models of ischemia and reperfusion have shown that statins have early cardioprotective effects. However, the effect of statin use within the first 24 hours of admission on early morbidity and mortality in AMI has not been well studied. Data were collected on 300,823 patients who had AMI in the National Registry of Myocardial Infarction 4. In-hospital events were compared between patients who continued statin therapy received before the index AMI hospitalization (n = 17,118) or newly started statin therapy within the first 24 hours of hospitalization (n = 21,978) and patients who did not receive early statin treatment (n = 126,128) or whose statin therapy was discontinued (n = 9,411). New or continued treatment with a statin in the first 24 hours was associated with a decreased risk of mortality compared with no statin use (4.0% and 5.3% compared with 15.4% no statin). Discontinuation of statin treatment was associated with a slightly increased risk of mortality (16.5%). Early statin use was also associated with a lower incidence of cardiogenic shock, arrhythmias, cardiac arrest, rupture, but not recurrent myocardial infarction. Propensity analysis yielded mortality odds ratios of 0.46 for continued therapy, 0.42 for newly started therapy, and 1.25 for discontinued therapy for matched pairs versus no statin therapy (all p values <0.0001). In conclusion, the use of statin therapy within the first 24 hours of hospitalization for AMI is associated with a significantly lower rate of early complications and in-hospital mortality.
Collapse
Affiliation(s)
- Gregg C Fonarow
- The Ahmanson-UCLA Cardiomyopathy Center, UCLA Division of Cardiology, Los Angeles, California, USA.
| | | | | | | | | | | | | |
Collapse
|
|
19
|
Abstract
Atherosclerosis is a multifactorial condition that can result in cardiovascular disease. Statin therapy is thought to mediate cardioprotective effects that influence endothelial function, inflammatory responses, plaque stability and thrombus formation, processes involved in atherosclerosis. Although reduction in low-density lipoprotein cholesterol (LDL-C) potentially plays a role in all of these effects, several lines of evidence also implicate nonlipidmediated 'pleiotropic' effects. For example, statin therapy confers a lower risk for coronary heart disease than placebo in patients with comparable serum cholesterol levels, and confers a greater magnitude of clinical benefit than expected based on LDL-C levels alone. Moreover, while nonstatin lipid-lowering therapy does not necessarily reduce stroke risk, statins have shown a significant reduction in stroke. Statins exert their pleiotropic effects, in part, by improving endothelial function via up-regulation of endothelial nitric oxide synthase enzyme activity. Markers of inflammation such as high sensitivity C-reactive protein have been also shown to add further prognostic information about patients at risk of cardiovascular disease who may benefit from statin therapy. Further studies are still needed to determine whether statins have direct effects on inflammatory pathways.
Collapse
Affiliation(s)
- J K Liao
- Vascular Medicine Research, Brigham & Women's Hospital, Harvard Medical School, 65 Landsdowne Street, Room 275, Cambridge, Massachusetts 02139, USA.
| |
Collapse
|
|
20
|
Perings SM, Grubert N, Kleinbongard P, Reinecke P, Schulz R, Hermsen D, Willers R, Kelm M. Chronic treatment with fluvastatin improves smooth muscle dilatory function in genetically determined hyperlipoproteinemia. J Cardiovasc Pharmacol 2004; 43:183-90. [PMID: 14716204 DOI: 10.1097/00005344-200402000-00004] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
We hypothesized that the HMG-CoA reductase inhibitor fluvastatin, does not only improve endothelium-dependent vasorelaxation, but that it also increases vascular smooth muscle reactivity in hyperlipoproteinemia. New Zealand White (NZW) rabbits aged 37 weeks (control), Watanabe Heritable Hyperlipidemic rabbits (WHHL) aged 37 weeks, and WHHL aged 35 weeks with fluvastatin treatment of 17 weeks (10 mg/kg/d) were examined. Aortas were isolated for isometric tension recording. Both endothelium-dependent and independent relaxation were impaired in WHHL. Fluvastatin significantly restored impaired endothelium-independent relaxation (WHHL: 57 +/- 12 versus WHHL+ fluvastatin: 150 +/- 22%; P < 0.05) and in tendency endothelium-dependent relaxation (WHHL: 26 +/- 5 versus WHHL+ fluvastatin: 83 +/- 29%; (P = 0.07)). In parallel, fluvastatin restored nitrite plasma level in hyperlipoproteinemic animals (WHHL: 480 (13-3821) versus WHHL+ fluvastatin: 808 (467-1595) nmol; P < 0.05). Thus, chronic treatment with fluvastatin not only improves endothelial but also vascular smooth muscle function in hyperlipoproteinemia, which may contribute to the beneficial clinical effects of statins.
Collapse
Affiliation(s)
- Stefan Martin Perings
- Department of Medicine, Division of Cardiology, Pulmonary Disease, and Angiology, Heinrich Heine University, Düsseldorf, Germany.
| | | | | | | | | | | | | | | |
Collapse
|
|
21
|
Mungall MMB, Gaw A, Shepherd J. Statin therapy in the elderly: does it make good clinical and economic sense? Drugs Aging 2003; 20:263-75. [PMID: 12641482 DOI: 10.2165/00002512-200320040-00003] [Citation(s) in RCA: 17] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/24/2023]
Abstract
HMG-CoA reductase inhibitors (statins) have been established as the dominant treatment for coronary heart disease (CHD). This dominance is based on an impressive body of clinical trial evidence showing significant benefits in primary prevention of cardiovascular events in individuals at risk for CHD and in secondary prevention of such events in patients with CHD and high or normal plasma cholesterol levels. There is, however, significant room for improvement in the treatment of CHD with respect both to drug efficacy and to the disparity between evidence-based medicine and actual clinical practice particularly in relation to treatment strategies for the elderly. Current statins fall short of requirements for 'ideal' lipid-lowering treatment in several respects; 'super' statins and other agents currently in development may satisfy more of these requirements. Moreover, available therapies are not applied optimally, because of physician nonacceptance and/or patient noncompliance; thus, the majority of patients with CHD or its risk factors still have cholesterol levels that exceed guideline targets. There is also evidence that older patients with CHD, or at high risk of CHD, are undertreated - possibly because of concerns regarding the increased likelihood of adverse events or drug interactions or doubts regarding the cost effectiveness of statin therapy in this population. This group is of particular clinical relevance, since it is showing a proportionate rapid expansion in most national populations. To address their potential healthcare needs, the ongoing Pravastatin in the Elderly at Risk (PROSPER) study is assessing the effects of pravastatin in elderly patients (5804 men and women aged 70-82 years) who either have pre-existing vascular disease or are at significant risk for developing it, with the central hypothesis that statin therapy (pravastatin 40 mg/day) will diminish the risk of subsequent major vascular events compared with placebo. After a 3.2-year treatment period, a primary assessment will be made of the influence of statin treatment on major cardiovascular events (a combination of CHD death, nonfatal myocardial infarction, and fatal or nonfatal stroke). Optimal deployment of the currently available agents and of newer agents (no matter how well they satisfy requirements for ideal treatment) ultimately depends on the establishment of an evidence base and may require far-reaching educational programmes that change the way risk factor management is viewed by caregivers and patients alike.
Collapse
|
|
22
|
Sasaki M, Bharwani S, Jordan P, Joh T, Manas K, Warren A, Harada H, Carter P, Elrod JW, Wolcott M, Grisham MB, Alexander JS. The 3-hydroxy-3-methylglutaryl-CoA reductase inhibitor pravastatin reduces disease activity and inflammation in dextran-sulfate induced colitis. J Pharmacol Exp Ther 2003; 305:78-85. [PMID: 12649355 DOI: 10.1124/jpet.102.044099] [Citation(s) in RCA: 64] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/12/2023] Open
Abstract
The dextran sulfate (DSS) model of colitis causes intestinal injury sharing many characteristics with inflammatory bowel disease, e.g., leukocyte infiltration, loss of gut epithelial barrier, and cachexia. These symptoms are partly mediated by entrapped leukocytes binding to multiple endothelial adhesion molecules (MAdCAM-1, VCAM-1, ICAM-1, and E-selectin). Pravastatin, an 3-hydroxy-3-methylglutaryl (HMG)-CoA reductase inhibitor, has anti-inflammatory potency in certain inflammation models; therefore, in this study, we measured the effects of pravastatin in DSS-induced colitis. The administration of pravastatin (1 mg/kg) relieved DSS-induced cachexia, hematochezia, and intestinal epithelial permeability, with no effect on serum cholesterol. Histopathologically, pravastatin prevented leukocyte infiltration and gut injury. Pravastatin also blocked the mucosal expression of MAdCAM-1. DSS treatment promoted mucosal endothelial nitric-oxide synthase (eNOS) mRNA degradation, an effect that was blocked by pravastatin. Importantly, the protective effects of pravastatin in DSS-induced colitis were not found in eNOS-deficient mice. Our results demonstrate that HMG-CoA reductase inhibitors preserve intestinal integrity in colitis, most likely via increased eNOS expression and activity, independent of cholesterol metabolism.
Collapse
Affiliation(s)
- Makoto Sasaki
- Department of Molecular and Cellular Physiology, Louisiana State University Health Sciences Center, Shreveport, Louisiana 71130-3932, USA
| | | | | | | | | | | | | | | | | | | | | | | |
Collapse
|
|
23
|
Abstract
The endothelium is a dynamic organ and responds to various physical and humoral conditions. The endothelium secretes several biologically active substances, both vasoconstrictors and vasodilators, which control these processes. Endothelial function is most commonly assessed as the vasodilatory response to stimuli. Several endothelium-dependent agonists have been identified, each of which acts through a membrane receptor. Nitric oxide which is continuously synthesized by the endothelium has a wide range of biological properties that maintain vascular homeostasis. It is a potent vasodilator and inhibitor of platelet aggregation and thus has an important protective role. Endothelial dysfunction in hypercholesterolemic patients is in large part due to a reduced bioavailability of NO. Traditional coronary risk factors, especially hypercholesterolemia, produce endothelial dysfunction even in patients with normal blood vessels. The underlying mechanisms involve a local inflammatory response, release of cytokines and growth factors, activation of oxidation-sensitive mechanisms in the arterial wall, modulation of intracellular signaling pathways, increased oxidation of low-density lipoprotein cholesterol, and quenching of nitric oxide. Clinical studies have shown a significant improvement in endothelial dysfunction following lowering of serum cholesterol levels, infusion of nitric oxide donors like L-arginine and exercise training. Clinical trials are underway examining the role of endothelin-1 receptor antagonists like bosentan in the prevention of graft atherosclerosis.
Collapse
Affiliation(s)
- Sandeep T Laroia
- Department of Medicine, School of Medicine and Health Sciences, University of North Dakota, Fargo, ND 58102, USA
| | | | | | | |
Collapse
|
|
24
|
Wang TD, Chen WJ, Mau TJ, Lin JW, Lin WW, Lee YT. Attenuation of increased myocardial ischaemia-reperfusion injury conferred by hypercholesterolaemia through pharmacological inhibition of the caspase-1 cascade. Br J Pharmacol 2003; 138:291-300. [PMID: 12540519 PMCID: PMC1573676 DOI: 10.1038/sj.bjp.0705098] [Citation(s) in RCA: 29] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/19/2023] Open
Abstract
1. Hypercholesterolaemia has been shown to be associated with greater myocardial ischaemia-reperfusion injury, in which apoptosis and inflammation-mediated necrosis both play a key role. 2. Caspase-1 is involved in the activation of both apoptosis and inflammation, through the intermediate of interleukin-1beta (IL-1beta). We herein examined whether pharmacological inhibition of the caspase-1 cascade, using Ac-Tyr-Val-Ala-Asp-CH(2)Cl (Ac-YVAD.cmk), after myocardial ischaemia have greater protective effects on myocardial ischaemia-reperfusion injury in diet-induced hypercholesterolaemic rabbits. 3. Male rabbits fed with standard chow or chow supplemented with 0.5% cholesterol and 10% coconut oil for 8 weeks were subjected to 30 min of left circumflex artery occlusion followed by 4 h of reperfusion. An intravenous bolus of Ac-YVAD.cmk (1.6 mg kg(-1)) or vehicle was given 20 min after coronary occlusion. 4. Postischaemic administration of Ac-YVAD.cmk markedly decreased infarct size from 26+/-3% to 12+/-2% in normally fed rabbits (P=0.005) and from 41+/-6% to 14+/-2% in cholesterol-fed rabbits (P<0.001). 5. In the ischaemic non-necrotic area, treatment with Ac-YVAD.cmk markedly reduced the percentage of terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labelling (TUNEL)-positive cardiomyocytes from 15.5+/-0.8% to 2.2+/-0.1% in normally fed rabbits (P<0.001) and from 39.0+/-2.3% to 2.2+/-0.1% in cholesterol-fed rabbits (P<0.001). 6. Ac-YVAD.cmk treatment resulted in a reduction not only of IL-1beta and caspase-1, but also of caspase-3 in the ischaemic myocardium in both normally fed and cholesterol-fed rabbits. 7. No differences in infarct size, the percentage of TUNEL-positive cardiomyocytes, IL-1beta levels or activity of caspase-1 and caspase-3 were observed between Ac-YVAD.cmk-treated normally fed and cholesterol-fed rabbits. 8. This study demonstrates that injection of a selective caspase-1 inhibitor after myocardial ischaemia markedly reduced the detrimental effect conferred by hypercholesterolaemia on myocardial ischaemia-reperfusion injury by attenuating both necrotic as well as apoptotic cell death pathways through inhibition of IL-1beta production and activation of caspase-1 and caspase-3.
Collapse
Affiliation(s)
- Tzung-Dau Wang
- Division of Cardiology, Department of Internal Medicine, National Taiwan University Hospital, Taipei, 100, Taiwan, Republic of China
| | - Wen-Jone Chen
- Department of Emergency Medicine, National Taiwan University Hospital, Taipei, 100, Taiwan, Republic of China
| | - Tzan-Jr Mau
- Division of Cardiology, Department of Internal Medicine, National Taiwan University Hospital, Taipei, 100, Taiwan, Republic of China
| | - Jong-Wei Lin
- Division of Cardiology, Department of Internal Medicine, National Taiwan University Hospital, Taipei, 100, Taiwan, Republic of China
| | - Wan-Wan Lin
- Department of Pharmacology, College of Medicine, National Taiwan University, Taipei, 100, Taiwan, Republic of China
| | - Yuan-Teh Lee
- Division of Cardiology, Department of Internal Medicine, National Taiwan University Hospital, Taipei, 100, Taiwan, Republic of China
- Author for correspondence:
| |
Collapse
|
|
25
|
Wang TD, Chen WJ, Su SSY, Lo SC, Lin WW, Lee YT. Increased cardiomyocyte apoptosis following ischemia and reperfusion in diet-induced hypercholesterolemia: relation to Bcl-2 and Bax proteins and caspase-3 activity. Lipids 2002; 37:385-94. [PMID: 12030319 DOI: 10.1007/s1145-002-0906-2] [Citation(s) in RCA: 41] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/23/2022]
Abstract
It has been reported that apoptosis is a significant contributor to myocardial cell death as a result of reperfusion injury. However, whether the extent of cardiomyocyte apoptosis following ischemia and reperfusion varies in different pathophysiological backgrounds is still uncertain. In this study, we examined whether hypercholesterolemia increases the extent of myocardial reperfusion injury by aggravating cardiomyocyte apoptosis and the effects of hypercholesterolemia on the expression of Bcl-2 and Bax proteins and the activation of caspase-3. Twenty-eight male New Zealand white rabbits were fed standard chow (control, n = 14) or chow supplemented with 10% cholesterol (hypercholesterolemic, n = 14) for 8 wk. Anesthetized rabbits were then subjected to 30 min of left circumflex artery occlusion followed by 4 h of reperfusion. Apoptosis was identified as "DNA ladders" by gel electrophoresis and confirmed histologically using the terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labeling (TUNEL) assay. The infarct size (% of risk region) was significantly greater in hypercholesterolemic rabbits than in controls (39 +/- 6 vs. 23 +/- 2%, P = 0.02). Very few TUNEL-positive cardiomyocytes could be identified in the nonischemic regions in both groups, consistent with an absence of DNA laddering. In contrast, TUNEL-positive cardiomyocytes were significantly displayed in the ischemic, nonnecrotic myocardium, and DNA ladder occurred in all animals. The percentage of TUNEL-positive cardiomyocytes in the ischemic nonnecrotic myocardium was significantly higher in hypercholesterolemic rabbits compared with controls (40 +/- 5 vs. 17 +/- 11%, P < 0.001). Western blot analysis showed that, in the nonischemic myocardium, hypercholesterolemic rabbits exhibited an approximately 50% increase in the expression of Bcl-2 (P < 0.05), but not Bax, than control rabbits. However, compared with controls, hypercholesterolemic rabbits exhibited a more pronounced decrease in the expression of Bcl-2 (42 +/- 4 vs. 26 +/- 2%, P < 0.01) and a similar extent of increase in the expression of Bax in the ischemic myocardium. Furthermore, hypercholesterolemic rabbits were associated with a markedly increased activation of caspase-3 within the ischemic myocardium compared to control rabbits. This study demonstrates that although hypercholesterolemia is associated with an increased myocardial Bcl-2/Bax ratio at baseline, it still significantly exacerbates cardiac reperfusion injury, not only by increasing the infarct size but also by increasing the extent of cardiomyocyte apoptosis.
Collapse
Affiliation(s)
- Tzung-Dau Wang
- Department of Internal Medicine Cardiology, National Taiwan University Hospital, Taipei, Republic of China
| | | | | | | | | | | |
Collapse
|
|
26
|
Tokumura A, Kanaya Y, Kitahara M, Miyake M, Yoshioka Y, Fukuzawa K. Increased formation of lysophosphatidic acids by lysophospholipase D in serum of hypercholesterolemic rabbits. J Lipid Res 2002. [DOI: 10.1016/s0022-2275(20)30173-5] [Citation(s) in RCA: 44] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2022] Open
|
|
27
|
|
|
28
|
Jones SP, Lefer DJ. Cardioprotective actions of acute HMG-CoA reductase inhibition in the setting of myocardial infarction. ACTA PHYSIOLOGICA SCANDINAVICA 2001; 173:139-43. [PMID: 11678736 DOI: 10.1046/j.1365-201x.2001.00899.x] [Citation(s) in RCA: 37] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/20/2022]
Abstract
A known risk factor for the development of coronary artery disease and subsequent myocardial infarction is hypercholesterolaemia. The widespread nature of this phenomenon in the western world has led to the development of agents which reduce serum cholesterol levels. One such class of agents, HMG-CoA reductase inhibitors (statins) are very effective in cholesterol reduction. Recently, clinical and experimental evidence has amassed suggesting that patients taking statins receive cardiovascular benefits that occur independent of cholesterol reduction. Experimental data suggest that statins may increase levels of nitric oxide (NO) in vivo. This review will address the 'cholesterol-independent' vasculoprotective and cardioprotective effects of statins in animal models. Upon completion, the reader will be familiar with the proposed cholesterol-independent pathways of statins and understand that the cholesterol-independent benefits may arise from enhanced production of NO.
Collapse
Affiliation(s)
- S P Jones
- Department of Molecular and Cellular Physiology, Louisiana State University Health Sciences Center, Shreveport, LA 71130, USA
| | | |
Collapse
|
|
29
|
Scalia R, Gooszen ME, Jones SP, Hoffmeyer M, Rimmer DM, Trocha SD, Huang PL, Smith MB, Lefer AM, Lefer DJ. Simvastatin exerts both anti-inflammatory and cardioprotective effects in apolipoprotein E-deficient mice. Circulation 2001; 103:2598-603. [PMID: 11382730 DOI: 10.1161/01.cir.103.21.2598] [Citation(s) in RCA: 145] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
BACKGROUND Simvastatin attenuates ischemia and reperfusion in normocholesterolemic animals by stabilizing endothelial nitric oxide synthase activity and inhibiting neutrophil-mediated injury. Because endothelial dysfunction is a detrimental effect of hypercholesterolemia, we examined whether short-term treatment with simvastatin could inhibit leukocyte-endothelium interaction and attenuate myocardial ischemia-reperfusion injury in apoE-deficient (apoE(-/-)) mice fed a high-cholesterol diet. METHODS AND RESULTS We studied leukocyte-endothelium interactions in apoE(-/-) mice fed a normal or a high-cholesterol diet after short-term (ie, 18 hours) simvastatin treatment. We also studied simvastatin treatment in myocardial ischemia-reperfusion injury by subjecting apoE(-/-) mice to 30 minutes of ischemia and 24 hours of reperfusion. ApoE(-/-) mice fed a high-cholesterol diet exhibited higher blood cholesterol levels, which were not affected by short-term simvastatin treatment. However, the increased leukocyte rolling and adherence that occurred in cholesterol-fed apoE(-/-) mice (P<0.001 versus control diet) were significantly attenuated by simvastatin treatment (P<0.01 versus vehicle). Cholesterol-fed apoE(-/-) mice subjected to myocardial ischemia-reperfusion also experienced increased myocardial necrosis (P<0.01 versus control diet), which was significantly attenuated by simvastatin (P<0.01 versus vehicle). Simvastatin therapy also significantly increased vascular nitric oxide production in apoE(-/-) mice. CONCLUSIONS Simvastatin attenuates leukocyte-endothelial cell interactions and ameliorates ischemic injury in hypercholesterolemic mice independently of lipid-lowering actions.
Collapse
Affiliation(s)
- R Scalia
- Department of Physiology, Jefferson Medical College, Thomas Jefferson University, Philadelphia, PA, USA
| | | | | | | | | | | | | | | | | | | |
Collapse
|
|
30
|
Haak E, Abletshauser C, Weber S, Goedicke C, Martin N, Hermanns N, Lackner K, Kusterer K, Usadel KH, Haak T. Fluvastatin therapy improves microcirculation in patients with hyperlipidaemia. Atherosclerosis 2001; 155:395-401. [PMID: 11254910 DOI: 10.1016/s0021-9150(00)00567-0] [Citation(s) in RCA: 28] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/29/2022]
Abstract
The purpose of this study was to investigate the effect of fluvastatin on the microcirculation of patients with hyperlipidaemia (low-density lipoprotein cholesterol > 160 mg/dL, triglycerides < 350 mg/dl) inadequately controlled by diet. After a dietary run-in of 4 weeks, patients were randomised in a double-blind study to receive fluvastatin 40 mg twice daily (n = 24) or placebo (n = 24) for 12 weeks. The effect on microcirculation was assessed using capillary microscopy and laser Doppler fluxmetry at the nailfold at baseline and at 6 and 12 weeks after initiation of therapy. Capillaroscopy showed that fluvastatin improved microcirculation, i.e. time to peak flow during postocclusive reactive hyperaemia dropped from 19.7 +/- 7.2 s at baseline to 12.3 +/- 9.5 s at week 6 (P < 0.01) and 10.6 +/- 6.5 s at week 12 (P < 0.0001). These results were confirmed using laser Doppler fluxmetry to study microcirculation in thermoregulatory capillaries at the same site. A significant decrease in total and LDL-cholesterol was achieved during fluvastatin therapy. In conclusion, fluvastatin therapy improves microcirculation in nutritive as well as thermoregulatory capillaries in hypercholesterolaemic patients within 6 weeks.
Collapse
Affiliation(s)
- E Haak
- Medical Department I, Center of Internal Medicine, University-Hospital, Johann Wolfgang Goethe-University, Frankfurt/Main, Germany
| | | | | | | | | | | | | | | | | | | |
Collapse
|
|
31
|
González-Fernández F, Jiménez A, López-Blaya A, Velasco S, Arriero MM, Celdrán A, Rico L, Farré J, Casado S, López-Farré A. Cerivastatin prevents tumor necrosis factor-alpha-induced downregulation of endothelial nitric oxide synthase: role of endothelial cytosolic proteins. Atherosclerosis 2001; 155:61-70. [PMID: 11223427 DOI: 10.1016/s0021-9150(00)00535-9] [Citation(s) in RCA: 33] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 10/17/2022]
Abstract
Cardiovascular disease is accompanied by an impaired endothelium-dependent vasodilatory response. Loss of endothelial nitric oxide synthase (eNOS) expression may contribute to endothelial dysfunction. The aim of the present study was to analyze the effect of cerivastatin, a novel HMG CoA reductase inhibitor, on tumor necrosis factor-alpha (TNF-alpha)-induced downregulation of eNOS protein expression in bovine aortic endothelial cells (BAEC). TNF-alpha (10 ng/ml)- incubated BAEC showed a reduced expression of eNOS protein and decreased eNOS mRNA stabilization. This effect was associated with an increased binding activity of BAEC cytosolic proteins to the 3'-untranslated region (3'UTR) of eNOS mRNA. Cerivastatin prevented TNF-alpha-induced downregulation of eNOS protein expression in a concentration-dependent manner (10(-8) to 10(-5) M). Cerivastatin also prevented the binding of the cytosolic proteins to 3'-UTR of eNOS mRNA and was associated with eNOS mRNA stabilization. The reduced expression of eNOS protein by TNF-alpha was also prevented by coincubation with cycloheximide. In addition cycloheximide inhibited the binding activity of the cytosolic proteins to 3'-UTR of eNOS mRNA, suggesting the inducible character of the mentioned-cytosolic proteins. TNF-alpha stimulated the translocation of nuclear factor-kappaB (NF-kappaB), an effect that was not modified by cerivastatin. Furthermore, an inhibitor of NF-kappaB translocation, pyrrolidine dithiocarbamate failed to modify both the downregulation of eNOS expression and the increased binding activity of the cytosolic proteins to 3'-UTR of eNOS mRNA by TNF-alpha. The effect of cerivastatin on eNOS expression and the binding activity of the cytosolic proteins were reversed by coincubation with L-mevalonate. In conclusion, cerivastatin stabilized eNOS mRNA and upregulated eNOS expression in the endothelium, and this was associated with a decreased binding activity of cytosolic proteins to 3'-UTR of eNOS mRNA. The effect of cerivastatin on the regulation of eNOS expression was independent of NF-kappaB mobilization by TNF-alpha. These findings suggest that cerivastatin may have beneficial effects on the endothelial dysfunction associated with cardiovascular diseases beyond its effect on lowering cholesterol.
Collapse
Affiliation(s)
- F González-Fernández
- Cardiovascular Research and Hypertension Laboratory, Fundación Jiménez Díaz, Av Reyes Católicos 2, 28040, Madrid, Spain
| | | | | | | | | | | | | | | | | | | |
Collapse
|
|
32
|
Sekiya M, Funada J, Suzuki J, Watanabe K, Miyagawa M, Akutsu H. The influence of left ventricular geometry on coronary vasomotion in patients with essential hypertension. Am J Hypertens 2000; 13:789-95. [PMID: 10933571 DOI: 10.1016/s0895-7061(00)00269-7] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/20/2023] Open
Abstract
The objective of this study was to assess the influence of left ventricular (LV) geometric pattern on coronary vasomotion in patients with essential hypertension. We studied 34 hypertensive patients, who had never been treated, with angiographically normal coronary arteries. Patients were classified into four LV geometric patterns by echocardiography: normal, concentric remodeling, eccentric hypertrophy, and concentric hypertrophy. The responses of coronary vasomotion in left anterior descending artery to vasoactive agents (acetylcholine, isosorbide dinitrate, adenosine triphosphate) were examined using a Doppler guidewire and quantitative coronary angiography. The percent increase in coronary blood flow evoked with acetylcholine (endothelium-dependent vasomotion) showed lowest in concentric hypertrophy, followed by eccentric hypertrophy, concentric remodeling, and normal geometry. The significant linear relationship between acetylcholine-induced coronary blood flow and LV mass was noted. There was no difference in the percent increase in coronary blood flow evoked with isosorbide dinitrate (endothelium-independent vasomotion of conduit vessel) among the four groups. The percent increase in coronary blood flow evoked with adenosine triphosphate (endothelium-independent vasomotion of resistant vessel) was significantly lower in patients with concentric hypertrophy than in the other three groups. The results in this study suggest that coronary vasomotion may be associated with LV geometry in patients with hypertension. The endothelium-dependent vasodilation is impaired progressively as LV hypertrophy advances. The endothelium-independent vasodilation of microvessels is impaired only in concentric hypertrophy. This advanced abnormality of coronary vasomotion may contribute to the high cardiovascular morbidity and mortality in patients with concentric hypertrophy.
Collapse
Affiliation(s)
- M Sekiya
- Department of Cardiology, Ehime National Hospital, Japan.
| | | | | | | | | | | |
Collapse
|
|
33
|
Sun YP, Lu NC, Parmley WW, Hollenbeck CB. Effects of cholesterol diets on vascular function and atherogenesis in rabbits. PROCEEDINGS OF THE SOCIETY FOR EXPERIMENTAL BIOLOGY AND MEDICINE. SOCIETY FOR EXPERIMENTAL BIOLOGY AND MEDICINE (NEW YORK, N.Y.) 2000; 224:166-71. [PMID: 10865232 DOI: 10.1046/j.1525-1373.2000.22416.x] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/20/2022]
Abstract
Vascular endothelial dysfunction is an important early event in atherogenesis. To evaluate the effects of different levels of cholesterol-containing diets on vascular function and atherogenesis, 17 New Zealand White male rabbits were randomized into four groups: Control with noncholesterol, 10-week 0.5% (0.5C-10) or 1% cholesterol (1C-10), and 14-week 0.5% cholesterol (0.5C-14) feedings. After 10 or 14 weeks, the aortas were harvested for studies of vascular endothelial function and percentage surface lipid lesions. The 0.5% and 1% cholesterol feedings resulted in the same degree of hypercholesterolemia independent of the level and period of cholesterol feeding. There was a decreased trend in vascular endothelial-dependent relaxation to acetylcholine in cholesterol-fed rabbits. Fourteen-week cholesterol feeding induced the least vascular dilation at a concentration of 10-7 M acetylcholine (-38 +/- 3%, -23 +/- 4%, -23 +/- 2%, and -15 +/- 5% in control, 0.5C-10, 1C-10, and 0.5C-14 groups, respectively, P = 0.003). More cumulative exposure of arterial walls to cholesterol induced more surface lipid lesions in the aorta (r = 0.877, P < 0.001). There was a negative relationship between aortic lesions and vasodilation (r = -0.557, P = 0.020 for calcium ionophore; r = -0.463, P = 0.062 for acetylcholine). We conclude that the 0.5% and 1% cholesterol feedings induce similar degrees of hypercholesterolemia. However, aortic lipid lesions and vascular reactivity are dependent on cumulative exposure to cholesterol rather than serum cholesterol level only. Furthermore, decreased vascular endothelial relaxation in cholesterol-fed rabbits was related to lipid plaques in the aorta.
Collapse
Affiliation(s)
- Y P Sun
- Division of Cardiology, Department of Medicine, University of California San Francisco, San Francisco, California 94143, USA.
| | | | | | | |
Collapse
|
|
34
|
Eichstädt HW, Abletshauser CB, Störk T, Weidinger G. Beneficial effects of fluvastatin on myocardial blood flow at two time-points in hypercholesterolemic patients with coronary artery disease. J Cardiovasc Pharmacol 2000; 35:735-40. [PMID: 10813375 DOI: 10.1097/00005344-200005000-00009] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
Abstract
Hypercholesterolemia is a major risk factor initiating and accelerating atherosclerosis and leading to severe stages of coronary artery disease (CAD) with a high risk of cardiovascular events. We investigated the impact of lipid lowering in patients with hypercholesterolemia and evident CAD on clinically relevant parameters like myocardial perfusion. Myocardial imaging was performed with thallium-201 single photon-emission computed tomography at rest and after maximal bicycle exercise in 22 patients after a 4-week lead-in period, and after 12 and 24 weeks of therapy with fluvastatin. Perfusion defects occurred in all patients, indicating stress-induced myocardial ischemia. After 12 weeks of therapy, the perfusion of the ischemic segments increased by 26% (277+/-99 to 349+/-96 cpm; p < 0.001), whereas the value of the normal segments was augmented only by 4% (478+/-44 to 497+/-28 cpm; p < 0.05). The results slightly improved further after 24 weeks. Moreover, a subgroup analysis elucidated a more pronounced effect in patients without lipid-lowering premedication. This nonpretreated group (n = 11) revealed an improvement of ischemic segments at stress by 42% at week 24. In contrast, pretreated patients had an increase of only 18% (between groups, p < 0.05), indicating a carryover effect of premedication. In conclusion, short-term therapy with fluvastatin acts beneficially on impaired vascular function in hypercholesterolemic patients with CAD.
Collapse
Affiliation(s)
- H W Eichstädt
- Department of Imaging Cardiology and Nuclear Medicine, Humboldt-University, Berlin, Germany
| | | | | | | |
Collapse
|
|
35
|
Abstract
The beneficial effects of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (statins) on coronary events have generally been attributed to their hypocholesterolaemic properties. However, as mevalonate and other intermediates of cholesterol synthesis (isoprenoids) are necessary for cell proliferation and other important cell functions, effects other than cholesterol reduction may explain the pharmacological properties of statins. In the present review, we discuss the current knowledge on the nonlipid-related effects of statins, with a special emphasis on their potential benefits in different diseases, such as atherosclerosis and cancer. The mechanism(s) responsible for their favourable properties are also reviewed.
Collapse
Affiliation(s)
- S Bellosta
- Institute of Pharmacological Sciences, University of Milan, Italy
| | | | | | | | | |
Collapse
|
|
36
|
Williams KJ, Scalia R, Mazany KD, Rodrigueza WV, Lefer AM. Rapid restoration of normal endothelial functions in genetically hyperlipidemic mice by a synthetic mediator of reverse lipid transport. Arterioscler Thromb Vasc Biol 2000; 20:1033-9. [PMID: 10764669 DOI: 10.1161/01.atv.20.4.1033] [Citation(s) in RCA: 31] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
Endothelial dysfunction is a major pathophysiological consequence of hypercholesterolemia and other conditions. We examined whether a synthetic mediator of lipid transport from peripheral tissues to the liver (ie, the "reverse" pathway) could restore normal endothelial function in vivo. Using assays of macrovascular and microvascular function, we found that genetically hypercholesterolemic apolipoprotein E knockout mice exhibited key endothelial impairments. Treatment of the mice for 1 week with daily intravenous bolus injections of large "empty" phospholipid vesicles, which accelerate the reverse pathway in vivo, restored endothelium-dependent relaxation, leukocyte adherence, and endothelial expression of vascular cell adhesion molecule-1 to normal or nearly normal levels. These changes occurred despite the long-standing hyperlipidemia of the animals and the persistence of high serum concentrations of cholesterol-rich atherogenic lipoproteins during the treatment. Our results indicate that dysfunctional macrovascular and microvascular endothelium in apolipoprotein E knockout mice can recover relatively quickly in vivo and that accelerated reverse lipid transport may be a useful therapy.
Collapse
Affiliation(s)
- K J Williams
- Department of Medicine, Thomas Jefferson University, Philadelphia, PA 19107-6799, USA.
| | | | | | | | | |
Collapse
|
|
37
|
Schirger JA, Grantham JA, Kullo IJ, Jougasaki M, Wennberg PW, Chen HH, Lisy O, Miller V, Simari RD, Burnett JC. Vascular actions of brain natriuretic peptide: modulation by atherosclerosis and neutral endopeptidase inhibition. J Am Coll Cardiol 2000; 35:796-801. [PMID: 10716485 DOI: 10.1016/s0735-1097(99)00593-8] [Citation(s) in RCA: 46] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 10/17/2022]
Abstract
OBJECTIVES We sought to define the vascular actions of the cardiac hormone brain natriuretic peptide (BNP) on cellular proliferation and cyclic guanosine monophosphate (cGMP) in human aortic vascular smooth muscle cells (HAVSMCs). Secondly, we investigated BNP and acetylcholine (ACh) vasorelaxations in aortic rings from normal and atherosclerotic rabbits in the presence and absence of long-term oral inhibition of neutral endopeptidase (NEP). BACKGROUND The vascular actions of BNP are not well defined, despite the presence of its receptor in vascular smooth muscle and the upregulation of NEP, the ectoenzyme that degrades BNP, in the vascular wall in atherosclerosis. METHODS HAVSMCs stimulated with fetal calf serum (FCS) were pulsed with bromodeoxyuridine (BrdU) with and without BNP. The HAVSMCs were incubated in the presence and absence of BNP to assess cGMP. Vasorelaxations to BNP and ACh were assessed in rings in normal and atherosclerotic rabbits in the presence and absence of long-term oral inhibition of NEP, together with assessment of atheroma formation. RESULTS FCS-stimulated BrdU uptake in HAVSMCs was suppressed with BNP. BNP potentiated cGMP in HAVSMCs. BNP resulted in potent vasorelaxation in normal isolated aortic rings, which were impaired in atherosclerotic versus normal rabbits and preserved with NEP inhibition, which also decreased atheroma formation. Relaxations to ACh, which were also impaired in atherosclerosis, were preserved with inhibition of NEP. CONCLUSIONS We conclude that BNP potently inhibits vascular smooth muscle cell proliferation and potentiates the generation of cGMP. BNP potently relaxes the normal rabbit aorta, and this response is impaired in atherosclerosis but preserved with inhibition of NEP, together with a reduction in atheroma formation and preservation of relaxations to ACh.
Collapse
Affiliation(s)
- J A Schirger
- Department of Internal Medicine, Mayo Clinic and Foundation, Rochester, Minnesota 55905, USA
| | | | | | | | | | | | | | | | | | | |
Collapse
|
|
38
|
Girod WG, Jones SP, Sieber N, Aw TY, Lefer DJ. Effects of hypercholesterolemia on myocardial ischemia-reperfusion injury in LDL receptor-deficient mice. Arterioscler Thromb Vasc Biol 1999; 19:2776-81. [PMID: 10559025 DOI: 10.1161/01.atv.19.11.2776] [Citation(s) in RCA: 49] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
Hypercholesterolemia is a primary risk factor for atherosclerosis, coronary artery disease, and myocardial infarction. We subjected low density lipoprotein receptor-deficient (LDLr -/-) and control (wild-type) mice to 30 minutes of myocardial ischemia and 120 minutes of reperfusion. Myocardial infarction per area at risk (AAR) was noted under baseline conditions to be significantly (P<0.05) smaller in the LDLr -/- mice compared with wild-type mice (24.7+/-3. 2% and 38.8+/-4.3% of AAR, respectively). Subsequently, mice were fed a high-cholesterol diet (HCD) for 2 or 12 weeks, which resulted in significant increases in serum cholesterol levels in both LDLr -/- and wild-type groups. After 2 weeks of the HCD, the LDLr -/- mice demonstrated a significant elevation (P<0.01) in myocardial necrosis per AAR (50.2+/-5.36% of AAR) compared with the normal-diet LDLr -/- group, whereas the short-term HCD-fed wild-type mice demonstrated no significant difference from baseline. In contrast, wild-type mice fed the HCD for 12 weeks revealed a significant (P<0. 05) decrease in necrosis per AAR, which was 22.5+/-3.2% of the AAR in comparison with that in the normal-diet wild-type mice (38.8+/-4. 3% of AAR). LDLr -/- mice on the same long-term HCD showed a similar significantly (P<0.05) decreased infarct size, which was 13.2+/-4.0% of the AAR. In additional experiments, we determined that myocardial tissue total glutathione (GSH) levels were reduced after 2 weeks of the HCD and were significantly increased after 12 weeks of the HCD in the LDLr -/- mouse heart. These data suggest that short-term cholesterol feeding renders the myocardium of LDLr -/- mice more susceptible to ischemia-reperfusion injury, whereas more long-term hypercholesterolemia confers cardioprotection in the LDLr -/- mouse heart.
Collapse
Affiliation(s)
- W G Girod
- Department of Surgery, LSU Medical Center, Shreveport, LA 71130, USA
| | | | | | | | | |
Collapse
|
|
39
|
Abstract
The pathophysiology of the association between cholesterol and atherosclerosis has been thought to involve the deposition, modification, and cellular uptake of cholesterol. We now believe that the process begins with vascular injury and involves inflammation and vessel remodeling. The vascular endothelium actively regulates vascular tone, lipid breakdown, thrombogenesis, inflammation, and vessel growth, all of which are important factors in the development of atherosclerosis. Endothelial dysfunction promotes atherosclerosis through vasoconstriction, monocyte and platelet adhesion, thrombogenesis, and cytokine and growth factor stimulation and release. An important component of endothelial dysfunction is reduced availability of nitric oxide, which is caused by low-density lipoproteins, especially if they are oxidized. This reduced availability appears to occur through a combination of decreased production, abnormal signaling, and increased destruction by oxygen-free radicals. Concurrently, endothelium-mediated vasoconstrictors, adhesion molecules, cytokines, growth factors, and thrombogenic factors, such as endothelin, are increased by oxidized low-density lipoprotein. Several studies have shown improvements in endothelial function with cholesterol lowering, which may explain the early and substantial reductions in major cardiovascular events associated with cholesterol lowering.
Collapse
Affiliation(s)
- R A Vogel
- Department of Medicine, University of Maryland School of Medicine, Baltimore, USA
| |
Collapse
|
|
40
|
Lefer AM, Campbell B, Shin YK, Scalia R, Hayward R, Lefer DJ. Simvastatin preserves the ischemic-reperfused myocardium in normocholesterolemic rat hearts. Circulation 1999; 100:178-84. [PMID: 10402448 DOI: 10.1161/01.cir.100.2.178] [Citation(s) in RCA: 223] [Impact Index Per Article: 8.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
BACKGROUND Ischemia followed by reperfusion in the presence of polymorphonuclear leukocytes (PMNs) results in cardiac contractile dysfunction as well as cardiomyocyte injury. These deleterious effects are due in large part to endothelial dysfunction leading to the upregulation of cell adhesion molecules and subsequent neutrophil-endothelium interaction. At clinically relevant doses, simvastatin, an HMG-CoA reductase inhibitor, has been shown to lower serum cholesterol levels and normalize endothelial cell function. We wanted to test the effects of simvastatin on neutrophil-mediated cardiac dysfunction in a controlled model of myocardial ischemia-reperfusion. METHODS AND RESULTS This study examines the effects of simvastatin in a neutrophil-dependent isolated perfused rat heart model of ischemia (I) (20 minutes) and reperfusion (R) (45 minutes) injury. Administration of simvastatin 25 micrograms/rat improved coronary flow and preserved left ventricular developed pressure (LVDP) and dP/dtmax, indexes of cardiac contractile function. Final LVDP was 95+/-5 mm Hg in I/R hearts perfused with PMNs and simvastatin, compared with 49+/-4 mm Hg in PMN-perfused I/R hearts receiving only vehicle (P<0.001). In addition, simvastatin significantly reduced PMN accumulation in the ischemic myocardium (P<0.01). In PMN-perfused rat hearts after I/R, simvastatin also significantly attenuated P-selectin expression, CD18 upregulation in rat PMNs, and PMN adherence to rat vascular endothelium. Significant, although less potent, effects were obtained with pravastatin. CONCLUSIONS These results provide evidence that HMG-CoA reductase inhibitors are potent and effective cardioprotective agents that inhibit leukocyte-endothelial cell interactions and preserve cardiac contractile function and coronary perfusion after myocardial ischemia and reperfusion. Moreover, these effects are unrelated to the cholesterol-lowering action of this agent and appear to be mediated by enhanced endothelial release of NO.
Collapse
Affiliation(s)
- A M Lefer
- Department of Physiology, Jefferson Medical College, Thomas Jefferson University, Philadelphia, PA, USA
| | | | | | | | | | | |
Collapse
|
|
41
|
Rossoni G, Berti F, Trento F, Cattaneo F, Porta R, Pescador R, Ferro L. Chronic oral defibrotide counteracts hypercholesterolemia noxious effects on cardiovascular function in the rabbit. Thromb Res 1999; 94:327-38. [PMID: 10379821 DOI: 10.1016/s0049-3848(99)00009-2] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
The aim of the present work was to assess if the cardioprotective drug defibrotide could counteract the hypercholesterolemia noxious effects on cardiovascular function. Aortas and hearts from normal- or cholesterol-fed rabbits, treated or not with chronic oral defibrotide (100 mg/kg/day) for 45 days, were used in in vitro tests throughout the experiment. Hypercholesterolemia worsened: aorta stickiness toward polymorphonuclear leukocytes, aorta relaxation to acetylcholine, heart left ventricular end-diastolic pressure and coronary perfusion pressure, heart left ventricular diastolic pressure, acetylcholine and endothelin-1 activity on coronary perfusion pressure, and heart generation of 6-Keto-prostaglandin F1alpha. Oral defibrotide counteracted and/or obliterated the above hypercholesterolemia noxious effects. Particularly, oral defibrotide counteracted the parameters associated with early endothelial cell disfunction: that is, increased adherence of leukocytes to endothelium and endothelial vasorelaxation induced by acetylcholine, which acts through the release of endothelium-derived relaxing factor. These activities of defibrotide are probably exerted through the increased generation of prostacyclin. The fact that acetylcholine induced vasorelaxation is partially protected by oral defibrotide points to a partial rescue of endothelial ability to generate endothelium-derived relaxing factor, as acethylcoline acts through the release of endothelium-derived relaxing factor, by defibrotide itself. Defibrotide's endothelial protection could, in turn, explains why defibrotide protected cardiovascular function. This is not surprising as, in a few cases, endothelial dysfunction, observed in hypercholesterolemia, was found to be prevented or reversed, pharmacologically, by PN-2001-10, a calcium channel blocker, dipyridamole, and lovastatin.
Collapse
Affiliation(s)
- G Rossoni
- Department of Pharmacology, Chemotherapy and Medical Toxicology, University of Milan, Italy
| | | | | | | | | | | | | |
Collapse
|
|
42
|
Lisspers J, Sundin O, Hofman-Bang C, Nordlander R, Nygren A, Rydén L, Ohman A. Behavioral effects of a comprehensive, multifactorial program for lifestyle change after percutaneous transluminal coronary angioplasty: a prospective, randomized controlled study. J Psychosom Res 1999; 46:143-54. [PMID: 10098823 DOI: 10.1016/s0022-3999(98)00074-9] [Citation(s) in RCA: 71] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/01/2023]
Abstract
A group of 93 coronary patients recently treated with percutaneous transluminal coronary angioplasty (PTCA) were randomly assigned to either an intervention or a control group. Subjects in the intervention group participated in a comprehensive behaviorally oriented program aimed at achieving significant long-term changes in risk factor-related lifestyle behavior. Assessments of lifestyle behaviors, psychological factors, biological risk factors, and rehabilitation as well as secondary prevention endpoints were carried out, at inclusion and after 12 months. Results showed that the intervention patients, as compared with controls, improved significantly on measures assessing smoking, exercise, and diet habits. These self-rated changes were confirmed by weight reductions and improved exercise capacity, as well as by between-group differences in subclinical chest pain during an exercise test. However, few effects were found on the different psychological variables, as well as on morbidity or return to work.
Collapse
Affiliation(s)
- J Lisspers
- MidSweden University at Ostersund and Institute for Futures Studies, Stockholm, Sweden.
| | | | | | | | | | | | | |
Collapse
|
|
43
|
Hoshida S, Yamashita N, Kawahara K, Kuzuya T, Hori M. Amelioration by quinapril of myocardial infarction induced by coronary occlusion/reperfusion in a rabbit model of atherosclerosis: possible mechanisms. Circulation 1999; 99:434-40. [PMID: 9918532 DOI: 10.1161/01.cir.99.3.434] [Citation(s) in RCA: 38] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
BACKGROUND The increased severity of the myocardial injury produced by coronary occlusion-reperfusion in models of atherosclerosis is associated with an increase in leukocyte accumulation in the ischemic myocardium. Expression of P-selectin, an adhesion molecule involved in the interaction between leukocytes and endothelium, is increased in atherosclerotic vessels. Long-term angiotensin-converting enzyme (ACE) inhibition has been shown to reduce atherosclerotic vascular change in experimental models. METHODS AND RESULTS We examined changes in the size of the infarct resulting from coronary occlusion/reperfusion in normally fed and cholesterol-fed rabbits that were chronically treated with quinapril. Infarct size was significantly larger in the cholesterol-fed versus normally fed rabbits. ACE activity in the ischemic and nonischemic myocardium was significantly reduced by quinapril. Chronic quinapril administration significantly ameliorated the increased myocardial injury in cholesterol-fed rabbits. Quinapril administration markedly increased the myocardial cGMP content and reduced the myeloperoxidase activity in the border region of the ischemic myocardium in cholesterol-fed rabbits. The enhanced expression of P-selectin in myocardial tissue of cholesterol-fed rabbits was also effectively reduced by quinapril treatment. The above effects of quinapril were eliminated by blockade of bradykinin B2 receptors or inhibition of nitric oxide synthesis. CONCLUSIONS Chronic quinapril treatment ameliorated the severity of myocardial injury produced by coronary occlusion/reperfusion in cholesterol-fed rabbits, possibly because of reversal of the enhanced interaction between leukocytes and endothelium in the ischemic myocardium via a bradykinin-related pathway.
Collapse
Affiliation(s)
- S Hoshida
- Division of Cardiology, First Department of Medicine, Osaka University Medical School, Japan.
| | | | | | | | | |
Collapse
|
|
44
|
John GW, Colpaert FC, Valentin JP. Overview of the Pharmacological Properties of Daltroban, a Thromboxane A2/Prostanoid-Receptor Partial Agonist. ACTA ACUST UNITED AC 1998. [DOI: 10.1111/j.1527-3466.1998.tb00358.x] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/02/2023]
|
|
45
|
Schobel HP, Schmieder RE. Vasodilatory capacity of forearm resistance vessels is augmented in hypercholesterolemic patients after treatment with fluvastatin. Angiology 1998; 49:743-8. [PMID: 9756426 DOI: 10.1177/000331979804901006] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
Atherosclerotic vessels are characterized by endothelial and structural abnormalities as indicated by an impaired vasodilation to metabolic requirements. To determine whether effective treatment of hypercholesterolemia may improve vasodilatory capacity of resistance vessels, the authors examined the impact of 12 and 24 weeks of lipid-lowering therapy with the hepatic hydroxymethylglutaryl coenzyme A (HMG-CoA)-reductase inhibitor fluvastatin (40 to 80 mg/day) on the increment in forearm blood flow during reactive hyperemia in 24 hypercholesterolemic patients (mean age: 56 +/- 11 years; 15 men/9 women). Changes in forearm blood flow in response to reactive hyperemia were measured by venous occlusion plethysmography. Serum low-density lipoprotein (LDL)-cholesterol fell from 213 +/- 32 to 125 +/- 27 mg/dL (P<0.001) after 12 weeks and remained stable at a level of 125 +/- 18 mg/dL after 24 weeks of treatment. Baseline forearm blood flow was similar before and after 12 and 24 weeks of therapy. In contrast, forearm blood flow at peak reactive hyperemia was greater at week 12 (37.0 +/- 22.9 mL/min/100 mL; P<0.05), and at week 24 (47.1 +/- 33.5 mL/min/100 mL; P<0.05) than at week 0 (30.5 +/- 18.1 mL/min/100 mL). Compared with week 0 (defined as 100%), the percent change in forearm blood flow in response to reactive hyperemia was augmented at week 12 (171 +/- 144%; P<0.05 vs week 0) and at week 24 (218 +/- 228%; P<0.05 vs week 0). Thus, the lowering of high serum LDL cholesterol after short-term treatment with fluvastatin increased the blood flow responses during reactive hyperemia in forearm resistance vessels. These data indicate a beneficial effect of HMG-CoA reductase inhibition on structural wall properties of peripheral arteries in human atherosclerosis.
Collapse
Affiliation(s)
- H P Schobel
- Department of Internal Medicine IV, University of Erlangen-Nürnberg, Germany
| | | |
Collapse
|
|
46
|
Abstract
Oxidized LDLs (Ox-LDLs) inhibit endothelium-dependent dilation of isolated conduit arteries in a manner comparable to the impairment demonstrated in atherosclerotic vessels. However, it is not known whether the microvessels, which do not develop atherosclerotic lesions, are susceptible to Ox-LDL. Since endothelial release of NO plays an important role in vasodilation and since its dysfunction associated with atherosclerosis has been shown to extend into the coronary microcirculation, we hypothesized that Ox-LDLs impair endothelium-dependent vasodilation of coronary arterioles by reducing the synthesis and/or release of NO. To test this hypothesis, porcine subepicardial vessels (50 to 100 microm) were isolated, cannulated, and pressurized to 60 cm H2O without flow for in vitro study. Isolated vessels developed basal tone and dilated in a dose-dependent manner to the endothelium-dependent vasodilators serotonin, ATP, and ionomycin. These vasodilatory responses were inhibited by the NO synthase inhibitor NG-monomethyl-L-arginine and were subsequently reversed by extraluminal administration of the NO precursor L-arginine (3 mmol/L), suggesting the involvement of NO in these vasomotor responses. Intraluminal incubation of the vessels with native LDL (N-LDL) or Ox-LDL (1 mg protein/mL) significantly attenuated dilations to serotonin, ATP, and ionomycin. Ox-LDL produced more severe inhibition than did N-LDL, and the inhibitory effect was comparable to that of NG-monomethyl-L-arginine. The inhibitory effects of N-LDL and Ox-LDL were reversed by exogenous L-arginine (3 mmol/L) and were prevented by sodium dihydroxybenzene disulfonate (Tiron), a cell-permeable superoxide scavenger. In contrast, administration of the cell-impermeable superoxide scavenger superoxide dismutase prevented the inhibitory effect of N-LDL but not of Ox-LDL. In addition, the inhibitory effects of LDL were not restored by D-arginine or by removal of intraluminal LDL. Neither N-LDL nor Ox-LDL altered endothelium-independent vasodilation to sodium nitroprusside. These results indicate that coronary arterioles are susceptible to LDLs that specifically impair endothelium-dependent vasodilation by reducing NO synthesis. It is suggested that the initiation of superoxide anion production and the subsequent L-arginine deficiency may be responsible for the detrimental effect of LDL.
Collapse
Affiliation(s)
- T W Hein
- Department of Medical Physiology, Microcirculation Research Institute, Texas A&M University Health Science Center, College Station 77843-1114, USA
| | | |
Collapse
|
|
47
|
Scalia R, Appel JZ, Lefer AM. Leukocyte-endothelium interaction during the early stages of hypercholesterolemia in the rabbit: role of P-selectin, ICAM-1, and VCAM-1. Arterioscler Thromb Vasc Biol 1998; 18:1093-100. [PMID: 9672069 DOI: 10.1161/01.atv.18.7.1093] [Citation(s) in RCA: 81] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
The early effects of hypercholesterolemia on leukocyte-endothelium interaction were studied in vivo in the rabbit mesenteric microcirculation. Rabbits fed a 0.5% high-cholesterol (HC) diet showed elevated plasma cholesterol levels during the 1 to 2 weeks of HC feeding (P<0.001 versus control diet-fed rabbits). Intravital microscopy of mesenteric venules revealed that leukocyte rolling had increased 10-fold (P<0.001 versus control-fed group) at the end of the first week of the HC diet, which was sustained after 2 weeks of HC feeding (P<0.001 versus control-fed rabbits). Firm adherence of leukocytes to the endothelium was moderately increased after a 1-week period of hypercholesterolemia (P<0.05) but increased by 12-fold at 2 weeks (P<0.001 versus control diet-fed and P<0.01 versus 1-week HC-fed rabbits). Upregulation of the endothelial cell adhesion molecules P-selectin, intercellular adhesion molecule-1, and vascular cell adhesion molecule-1 was observed immunohistochemically on the intestinal microvascular endothelium of HC-fed rabbits. P-selectin was maximally expressed within the first week of the HC diet and remained elevated during the second week of cholesterol feeding (P<0.01 versus control). In contrast, intercellular adhesion molecule-1 and vascular cell adhesion molecule-1 were moderately upregulated at 1 week but were highly expressed after 2 weeks of the HC diet (P<0.05 and P<0.001 versus control, respectively). Basal release of NO from both mesenteric microvascular and aortic endothelium in cholesterol-fed rabbits was progressively reduced after 1 (P<0.05) and 2 (P<0.01) weeks. Our data suggest that enhanced leukocyte-endothelium interaction occurs in vivo in the rabbit microcirculation during the first 2 weeks of hypercholesterolemia. This phenomenon is associated with impaired basal NO release and progressive endothelial surface expression of endothelial cell adhesion molecules (ie, P-selectin, intercellular adhesion molecule-1, and vascular cell adhesion molecule-1) in the microvasculature.
Collapse
Affiliation(s)
- R Scalia
- Department of Physiology, Jefferson Medical College, Thomas Jefferson University, Philadelphia, PA 19107-6799, USA
| | | | | |
Collapse
|
|
48
|
Vakeva AP, Agah A, Rollins SA, Matis LA, Li L, Stahl GL. Myocardial infarction and apoptosis after myocardial ischemia and reperfusion: role of the terminal complement components and inhibition by anti-C5 therapy. Circulation 1998; 97:2259-67. [PMID: 9631876 DOI: 10.1161/01.cir.97.22.2259] [Citation(s) in RCA: 285] [Impact Index Per Article: 10.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
BACKGROUND Myocardial ischemia and reperfusion (MI/R)-induced tissue injury involves necrosis and apoptosis. However, the precise contribution of apoptosis to cell death, as well as the mechanism of apoptosis induction, has not been delineated. In this study, we sought to define the contribution of the activated terminal complement components to apoptosis and necrosis in a rat model of MI/R injury. METHODS AND RESULTS Monoclonal antibodies (mAbs; 18A and 16C) raised against the rat C5 complement component bound to purified rat C5 (ELISA). 18A effectively blocked C5b-9-mediated cell lysis and C5a-induced chemotaxis of rat polymorphonuclear leukocytes (PMNs), whereas 16C had no complement inhibitor activity. A single dose (20 mg/kg i.v.) of 18A blocked >80% of serum hemolytic activity for >4 hours. Administration of 18A before myocardial ischemia (30 minutes) and reperfusion (4 hours) significantly reduced (91%) left ventricular free wall PMN infiltration compared with 16C treatment. Treatment with 18A 1 hour before ischemia or 5 minutes before reperfusion significantly reduced infarct size compared with 16C treatment. A significant reduction in infarct size (42%) was also observed in 18A-treated rats after 30 minutes of ischemia and 7 days of reperfusion. DNA ladders and DNA labeling (eg, TUNEL assay) demonstrated a dramatic reduction in MI/R-induced apoptosis in 18A-treated compared with 16C-treated rats. CONCLUSIONS Anti-C5 therapy in the setting of MI/R significantly inhibits cell apoptosis, necrosis, and PMN infiltration in the rat despite C3 deposition. We conclude that the terminal complement components C5a and C5b-9 are key mediators of tissue injury in MI/R.
Collapse
Affiliation(s)
- A P Vakeva
- Haartman Institute, Department of Bacteriology and Immunology, University of Helsinki, Finland
| | | | | | | | | | | |
Collapse
|
|
49
|
Abstract
A high-pressure liquid chromatography (HPLC) assay for measuring picomole quantities of nitrosothiol in biological samples was developed. The assay utilizes the catalytic reduction of nitrosothiol by mercuric cation (Hg2+). Released nitrogen oxide reacts with sulfanilamide (SA) and N-(1-napthyl)ethylenediamine (NNED) to form a stable azo dye. The azo dye is then separated from N-(1-napthyl)ethylenediamine and quantified by reversed-phase HPLC. In addition to nitrosothiol, nitrite and atmospheric nitrogen oxides are sources of nitrogen oxide that react with the reagents, SA and NNED, to form the azo dye. Therefore, a reference sample, which includes the nitrosothiol sample and all reagents except Hg2+, is utilized for the subtraction of nitrite and atmospheric nitrogen oxides which "contaminate" the nitrosothiol sample and reagents. This method is a sensitive (approximately 3 pmol; approximately 10(-1) microM) and accurate means to measure nitrosothiol concentration in biologic samples.
Collapse
Affiliation(s)
- R K Goldman
- Department of Surgery, Oregon Health Sciences University, Portland 97201-3098, USA
| | | | | |
Collapse
|
|
50
|
Davignon J. Methods and endpoint issues in clinical development of lipid-acting agents with pleiotropic effects. Am J Cardiol 1998; 81:17F-24F. [PMID: 9604899 DOI: 10.1016/s0002-9149(98)00253-7] [Citation(s) in RCA: 14] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Affiliation(s)
- J Davignon
- Hyperlipidemia and Atherosclerosis Research Group, Clinical Research Institute of Montreal, QC, Canada
| |
Collapse
|