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Biomedical subjects

Michael Weis

Publications and source records attributed to Michael Weis.

At least 19 recordsLinked to original sources

Drugs modulating endothelial function after transplantation.

Endothelial cells play a vital role in the success or failure of a transplant procedure. The procedure itself can be viewed as a series of insults that damages the endothelium thereby triggering an inflammatory cascade that may, if uncontrolled, drive the proliferative and fibrotic processes characteristic of chronic graft vasculopathy. Unfortunately, many immunosuppressant agents contribute to this process. Glucocorticoids and the calcineurin inhibitor cyclosporine induce endothelial dysfunction, and although tacrolimus may not have the same disruptive effects on endothelial function as cyclosporine, its endothelial activity is still being established. In contrast, antiproliferative agents slow the proliferation and migration of endothelial cells and so help protect against graft vasculopathy. Researchers agree that endothelial cell dysfunction is a potentially treatable stage in the multifactorial process of graft vasculopathy and rejection. A number of cardiovascular agents (statins, angiotensin converting enzyme inhibitors, calcium channel blockers), immunoregulatory drugs, and dietary compounds have been shown to have beneficial effects on endothelial function. We briefly review the evidence supporting their use as protection for endothelial cells in transplant recipients.

Cardiovascular Agents↗

Coronary endothelial vasomotor function and vascular remodeling in heart transplant recipients randomized for tacrolimus or cyclosporine immunosuppression.

OBJECTIVES: This study aimed to compare changes in coronary endothelial function, systemic endothelin-1 (ET-1) levels, and vascular remodeling in heart transplant recipients randomized to cyclosporin A (CyA) or tacrolimus (Tac) immunosuppression. BACKGROUND: Functional endothelial abnormalities and intimal thickening are sensitive measures of early cardiac allograft vasculopathy (CAV). METHODS: The randomized, prospective study was performed in two groups of 22 patients, maintained on Tac or CyA and mycophenolate mofetil immunosuppression, 1 and 12 months after heart transplantation. We investigated epicardial luminal diameter, coronary blood flow velocity, and ET-1 plasma levels at 1 and 12 months after transplantation. Structural coronary alterations were determined using intravascular ultrasound. RESULTS: Epicardial vasomotor function at baseline and during follow-up was comparable between the groups. Deterioration of microvascular endothelial function during follow-up was significantly enhanced in the CyA versus Tac group (p < 0.05). Circulating ET-1 concentration increased in the CyA group but significantly decreased over time in the Tac group (CyA +17% vs. Tac -25%; p < 0.05). The time-dependent increase in mean intimal area was significantly enhanced in the CyA versus Tac group, whereas the vessel area significantly increased during follow-up in the Tac compared with the CyA group. CONCLUSIONS: Epicardial endothelial function is comparable between CyA- and Tac-treated patients. Microvascular endothelial function deteriorates more in CyA-treated patients, a finding that correlates with enhanced ET-1 concentration and an increased intimal area during follow-up. The mean vessel area in the Tac group increased over time, indicating positive vascular remodeling. Tac is superior to CyA with respect to microvascular endothelial function, intimal thickening, and vascular remodeling.

Adult↗

Expansion of circulating Toll-like receptor 4-positive monocytes in patients with acute coronary syndrome.

BACKGROUND: Atherosclerosis is an inflammatory disease in which monocytes and macrophages have been suggested to play an essential role. The underlying signaling mechanisms are unknown thus far. We hypothesized that the human isoform of Toll-like receptor (hTLR)-4 is involved in monocyte activation of patients with accelerated forms of atherosclerosis. METHODS AND RESULTS: Expression of hTLR4 on circulating monocytes from 30 controls, 20 patients with stable angina (SA), 40 patients with unstable angina (UA), and 28 patients with acute myocardial infarction (AMI) was compared with the use of flow-cytometry and reverse transcription-polymerase chain reaction. Regulation of interleukin (IL)-12 and B7-1 as downstream events of TLR4 activation was analyzed after lipopolysaccharide stimulation of monocytes. TLR4-transfected Chinese hamster ovary (CHO) cells were used to identify potential hTLR4 ligands in the serum of patients with UA or AMI. Circulating hTLR4+/CD14+ monocytes were approximately 2.5-fold increased above controls and patients with SA in the UA and AMI groups (P<0.0001). This was paralleled by enhanced transcript levels of TLR4 and Myd88 in patients with UA and AMI (P<0.0001) and increased expression of IL-12 (UA 35.5+/-7.8, AMI 31.8+/-7.7 versus SA 2.2+/-0.5, controls 2.1+/-0.3 pg/mL; P<0.0002) and B7-1 (UA 27.3+/-14.4, AMI 22.6+/-11.1 versus SA 3.4+/-2.5, controls 2.4+/-2.3%; P<0.0001). Compared with serum from patients with UA and AMI, challenging TLR4-transfected CHO cells with serum from SA patients yielded only a weak response (P<0.0001). Coincubation with anti-heat shock protein 60 inhibited CHO cell activation. CONCLUSIONS: UA and AMI are associated with enhanced expression and signaling events downstream of hTLR4 in circulating monocytes. These observations suggest hTLR4 activation as a signaling mechanism in immune-mediated progression of atherosclerosis.

Acute Disease↗

Statins decrease Toll-like receptor 4 expression and downstream signaling in human CD14+ monocytes.

OBJECTIVE: Anti-inflammatory effects of statins contribute to their clinical benefit. Molecular mechanisms underlying these effects have not been well explored. Because statins attenuate lipopolysaccharide (LPS) responsiveness, we hypothesized that part of the pleiotropic effects are mediated through innate immunity. METHODS AND RESULTS: Toll-like receptor (TLR) 4 expression and downstream signaling in CD14+ monocytes after incubation with simvastatin and atorvastatin were quantified via flow-cytometry, quantitative RT-PCR, kinase assay, and enzyme-linked immunosorbent assay. Incubation with intermediates/ inhibitors of the mevalonate pathway was used to identify the mode of statin action. Statin incubation resulted in a dose-dependent reduction of TLR4 expression (53+/-7.6% reduction compared with untreated monocytes; P<0.005), transcript levels (68+/-6.3%; P<0.002), decreased IRAK phosphorylation (37+/-8.3%; P<0.05), and LPS-induced IL-6, IL-12, tumor necrosis factor (TNF)-alpha, and B7-1 expression (P<0.05). Four weeks of treatment with atorvastatin significantly reduced TLR4 expression on circulating CD14+ monocytes by 36.2+/-4.2% (P<0.05). Effects of statins were reversed by mevalonate (P=0.57). Incubation with specific inhibitors of geranylgeranyltransferase (54+/-4.3%), farnesyltransferase (57+/-5.1%), or with clostridium-difficile toxin B (58+/-6.1%, P<0.01) imitated the statin effects. Whereas wortmannin and LY294002 inhibited the statin effect (P=0.27), incubation with a specific RhoA kinase inhibitor had no effect (P=0.57). CONCLUSIONS: Statins influence TLR4 expression and signaling via inhibition of protein geranylgeranylation and farnesylation. These observations imply interactions with innate immunity as one pleiotropic mechanism.

1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine↗

Vasospastic angina pectoris associated with Churg-Strauss syndrome.

BACKGROUND: A 50-year-old woman presented with recurrent episodes of unstable angina pectoris refractory to vasodilator treatment. Relevant coronary stenoses were excluded by coronary angiography and intravascular ultrasonography. Intracoronary infusion of acetylcholine revealed diffuse coronary vasospasms associated with clinical signs of myocardial ischemia and ST-segment elevation. Symptoms of bronchial asthma, polyneuropathy, nasal polyps, allergic rhinitis, gastritis and eosinophilia led to a diagnosis of Churg-Strauss syndrome. INVESTIGATIONS: Serum chemistry, coronary angiography, left-heart catheterization, intravascular ultrasonography and coronary vasospasm provocation with acetylcholine. DIAGNOSIS: Vasospastic angina pectoris associated with Churg-Strauss syndrome. MANAGEMENT: Treatment with systemic corticosteroids and cyclophosphamide.

Adrenal Cortex Hormones↗

Role of cytokines in cardiovascular diseases: a focus on endothelial responses to inflammation.

Complex cellular and inflammatory interactions are involved in the progress of vascular diseases. Endothelial cells, upon exposure to cytokines, undergo profound alterations of function that involve gene expression and de novo protein synthesis. The functional reprogramming of endothelial cells by cytokines is of importance especially in patients with chronic vascular inflammation. The intercellular network of dendritic cells, T-lymphocytes, macrophages and smooth muscle cells generates a variety of stimulatory cytokines [e.g. TNF-alpha (tumour necrosis factor-alpha), IL (interleukin)-1, IL-6 and IFN-gamma (interferon-gamma)] and growth factors that promote the development of functional and structural vascular changes. High concentrations of proinflammatory cytokines increase oxidative stress, down-regulate eNOS (endothelial nitric oxide synthase) bioactivity and induce endothelial cell apoptosis. Chemoattractant cytokines [e.g. VEGF (vascular endothelial growth factor), TGF-beta1 (transforming growth factor-beta1) and IL-8] are important regulators of inflammation-induced angiogenesis and are directly modulated by nitric oxide. This review will focus on the vascular mechanisms orchestrated by cytokines and summarizes the current knowledge concerning the contribution of cytokines to cardiovascular diseases.

Cardiovascular Diseases↗

The impact of immunosuppression on endothelial function.

Endothelial dysfunction is an early marker for transplant atherosclerosis. Potential mechanisms for allograft endothelial dysfunction include stimulation of alloimmune-dependent pathways, ischemia/reperfusion injury, metabolic alterations, chronic infections, as well as direct endothelial cell activation by immunosuppressive drugs. Thus far, no study has directly compared different immunosuppressive drugs with respect to their potential to modulate endothelial function under normoxic and hypoxic conditions. We examined human microvascular endothelial cells (HMEC-1) in vitro after stimulation with therapeutic concentrations of methylprednisolone (MP), mycophenolic acid (MMF), cyclosporine A (CS), rapamycin (Rapa), and tacrolimus (Tac) to designate the corresponding induction of oxidative stress, apoptosis, metabolic activity, proliferation, endothelin (ET-1) release, and nitric oxide (NO) production. HMEC-1 stimulation with CS, MMF, and Rapa resulted in a stronger induction of oxidative stress compared with MP and Tac. Induction of oxidative stress by immunosuppressives correlated with metabolic activity and apoptosis. Low- and high-dose MMF significantly inhibited cell proliferation under hypoxic conditions, whereas low-dose CS and MP increased endothelial cell proliferation. ET-1 release was significantly elevated by Rapa, Tac, and MP. NO production was significantly enhanced by all immunosuppressive drugs except Tac. Quality and quantity of immunosuppression modify endothelial function and lead to a dose-dependent and oxygenation-state-related endothelial activation. MP and MMF induced minor changes in endothelial function compared with CS, Rapa, and Tac.

Apoptosis↗

Dendritic cell adhesion is enhanced on endothelial cells preexposed to calcineurin inhibitors.

Chronic rejection remains a major complication in solid organ transplantation. Host alloreactive T cells (TC) can be activated by donor dendritic cells (DCs; direct allorecognition) or by recipient DCs (indirect allorecognition). A fundamental aspect of DC function is vascular invasion to present donor antigens to recipient naive TC in secondary lymphoid organs. We investigated the impact of calcineurin inhibitors on DC binding and transmigration to allogeneic human microvascular endothelial cells (ECs) with and without blocking of specific adhesion molecules. Recipient immature DCs were generated by culturing CD14 human peripheral blood monocytes with GM-CSF and IL-4. DC adhesion and transmigration were investigated on allogeneic ECs preincubated with increasing concentrations of cyclosporine and tacrolimus. Experiments were repeated in the presence of blocking antibodies against LFA-1, PECAM-1, VCAM-1, and ICAM-1. Endothelial stimulation with cyclosporine A (100 and 300 ng/mL) and tacrolimus (15 ng/mL) significantly enhanced DC-EC adhesion and transmigration (P<0.01). LFA-1 blockade on DCs significantly reduced cyclosporine- and tacrolimus-induced DC adhesion (P<0.001). VCAM-1 blockade on ECs partially reversed cyclosporine-induced DC adhesion (P<0.001), whereas DC adhesion under tacrolimus exposure was significantly decreased by ICAM-1 (P<0.01) and PECAM-1 (P<0.001) blockade. DC binding and transmigration on allogeneic ECs exposed to calcineurin inhibitors is concentration-dependently increased. Different adhesion molecule patterns on ECs are responsible for enhanced DC invasion under cyclosporine and tacrolimus exposure. We speculate that long-term immunosuppression mediates enhanced invasion of recipient DCs to the donor organ and therefore may aggravate chronic rejection.

Antibodies, Blocking↗

Cytomegalovirus infection in heart transplant recipients is associated with impaired endothelial function.

BACKGROUND: Cardiac allograft vasculopathy (CAV) is initiated by allograft endothelial injury. We hypothesized that a major mechanism by which cytomegalovirus (CMV) could contribute to CAV is by dysregulation of the endothelial vasomotor response. METHODS: Coronary endothelial vasomotor function was determined in 183 consecutive patients (24+/-33 months after transplantation), and was correlated with recipient and donor CMV serological status before transplantation and with documented CMV infection episodes (CMVpp65Ag+). Serial endothelial function measurements were performed in a subgroup of 53 transplant recipients (1 month and 12 months after transplantation). The composite endpoint of cardiovascular related events and death during a follow-up of 66+/-41 months was analyzed based on the CMV serological status before transplantation. RESULTS: The medium event-free time for CMV-negative recipients of CMV-positive hearts was 8.1 years compared with 13.3 years for the other groups (P<0.05). Distal epicardial but not microvascular endothelial function was significantly impaired in CMV seronegative recipients of seropositive donor hearts (n=48) compared with all other groups (P<0.01 versus seronegative recipient/seronegative donor; P<0.05 versus seropositive recipient/seronegative donor; P<0.05 versus seropositive recipient/seropositive donor). Distal epicardial endothelial dysfunction was more pronounced in heart transplant recipients with a history of documented CMV infection compared with patients without any documented CMV infection (P<0.01). In a longitudinal subgroup analysis, distal epicardial and microcirculatory endothelial vasomotor response deteriorated significantly in recipients with documented CMV infection (P<0.05 versus baseline) but not in patients without previous CMV infection. CONCLUSIONS: Documented CMV infection episodes in heart transplant recipients are associated with impaired coronary endothelial function. CMV-negative recipients of CMV-positive donor hearts have an impaired distal epicardial endothelial function and an increased incidence of cardiovascular-related events and death during follow-up. CMV infection may contribute to allograft failure by accelerating coronary endothelial dysfunction.

Adult↗

Tacrolimus or cyclosporine: which is the better partner for mycophenolate mofetil in heart transplant recipients?

BACKGROUND: The aim of this single-center study was to investigate whether trough level adjusted mycophenolate mofetil (MMF) is more efficacious in combination with tacrolimus (TAC) or cyclosporine (CsA) and to evaluate the impact of either drug on MMF dosage. METHODS: Sixty patients (TAC, n = 30; CsA, n = 30) undergoing heart transplantation were randomized into a prospective, open-label, controlled trial. Immunosuppression consisted of TAC or CsA in combination with MMF and corticosteroids. Target blood trough levels of TAC, CsA, and mycophenolic acid (MPA) were in the range of 10 to 15 ng/mL, 100 to 300 ng/mL, and 1.5 to 4.0 microg/mL, respectively. Acute rejection episodes (ARE); survival data; and adverse events with a special emphasis on infections, diabetes, hypertension, hypercholesterolemia, and the development of graft vessel disease (GVD) were recorded. RESULTS: Baseline characteristics were well balanced. All patients were successfully withdrawn from corticosteroids within 6 months of transplant. Freedom from acute rejection was significantly higher (P = 0.0001) and the incidence of ARE per 100 patient days significantly lower in the TAC-MMF group than in the CsA-MMF group (0.03 vs. 0.15; P = 0.00007). Overall patient survival during follow-up was similar (93% vs. 90%). To achieve the targeted MPA blood levels, a significantly lower dose of MMF was required for TAC versus CsA patients. After a follow-up time of 2 years, the mean GVD score was 1.85 +/- 3.18 in the TAC-MMF group and 3.95 +/- 4.8 in the CsA-MMF group (P = 0.08). CONCLUSIONS: At the selected doses and target levels for TAC and CsA used in this study, trough level adjusted MMF was more efficacious in combination with TAC for prevention of ARE. Furthermore, CsA patients need significantly more MMF to achieve similar MPA levels.

Adult↗

Beneficial effects of quinaprilat on coronary vasomotor function, endothelial oxidative stress, and endothelin activation after human heart transplantation.

BACKGROUND: We evaluated the potential of angiotensin-converting enzyme inhibition (ACEI) to modulate resting coronary vasomotor tone and endothelial dysfunction, and to decrease vascular oxidative stress and endothelin (ET)-1 activity in human heart transplant recipients. METHODS: Coronary vasomotor responses and transcardiac metabolism of glutathione, oxidized glutathione, and ET-1 were determined before and after quinaprilat infusion in 32 heart transplant recipients. Furthermore, the potential effects of ACEI on endothelial oxidative stress, ET-1 activity, and nitrosoglutathione formation were investigated using endothelial cell cultures. RESULTS: Epicardial diameter increased in response to quinaprilat by 6% +/- 1% (proximal segments; P<0.05) and 14% +/- 3% (distal segments; P<0.01). Coronary flow velocity increased by 2.2 +/- 0.2 (P<0.03). Coronary vasodilation to quinaprilat was negatively correlated with preexisting functional and structural coronary alterations. Quinaprilat selectively improved epicardial vasomotor response in segments with endothelial dysfunction, whereas microvascular endothelial dysfunction was unchanged. Transcardiac glutathione and big ET levels decreased after quinaprilat, whereas oxidized glutathione and ET-1 concentrations remained unchanged. Cell culture studies showed antioxidative effects of quinaprilat, revealed concentration-dependent down-regulation of endothelial ET-1 release, and indicated formation of nitrosoglutathione by quinaprilat. CONCLUSION.: ACE regulates resting coronary vasomotor tone. Quinaprilat reduces vascular oxidative stress and ET-1 activity and mediates formation of nitrosoglutathione, effects that might contribute to long-term vasculoprotective effects of ACEI after heart transplantation.

Adult↗

Cytomegalovirus infection impairs the nitric oxide synthase pathway: role of asymmetric dimethylarginine in transplant arteriosclerosis.

BACKGROUND: We hypothesized that cytomegalovirus (CMV) may contribute to the vasculopathy observed in cardiac allograft recipients by impairing the endothelial nitric oxide synthase pathway. We focused on asymmetric dimethylarginine (ADMA, the endogenous inhibitor of nitric oxide synthase) as a potential mediator of the adverse vascular effect of CMV. METHODS AND RESULTS: Heart transplant recipients manifested elevated plasma ADMA levels compared with healthy control subjects. Transplant patients with CMV DNA-positive leukocytes had higher plasma ADMA concentrations and more extensive transplant arteriopathy (TA). Human microvascular endothelial cells infected with the CMV isolates elaborated more ADMA. The increase in ADMA was temporally associated with a reduction in the activity of dimethylarginine dimethylaminohydrolase (DDAH, the enzyme that metabolizes ADMA). Infected cultures showed high levels of oxidative stress with enhanced endothelial production of superoxide anion. CONCLUSIONS: CMV infection in human heart transplant recipients is associated with higher ADMA elevation and more severe TA. CMV infection in endothelial cells increases oxidative stress, impairs DDAH activity, and increases ADMA elaboration. CMV infection may contribute to endothelial dysfunction and TA by dysregulation of the endothelial nitric oxide synthase pathway.

Amidohydrolases↗

Cardiac allograft vasculopathy and dysregulation of the NO synthase pathway.

Cardiac allograft vasculopathy is the most aggressive form of atherosclerosis in humans and is the leading cause of death after the first year of heart transplantation. Endothelial dysfunction is a major contributing factor to the acceleration of coronary vascular disease in these individuals. A reflection of this endothelial dysfunction is the severe impairment in endothelium-dependent vasodilation that occurs early after transplantation. The etiology of this allograft endothelial alteration is multifactorial and may include preexisting atherosclerosis of the graft vessels, reperfusion injury during transplantation, denervation, disruption of the lymphatic system, and acute and chronic immune injury, as well as traditional risk factors for coronary artery disease (hyperlipidemia, diabetes, hypertension, or hyperhomocysteinemia) and pathogens, such as cytomegalovirus. The alteration in endothelial function affects vasomotor tone of the coronary arteries. Evidence indicates that there may be an impairment of endothelial production and/or activity of NO. Because NO is a potent vasodilator, its deficiency would explain the abnormal vasomotor tone in these individuals. In addition, because NO inhibits key processes in vascular inflammation and atherosclerosis, its absence may contribute to the acceleration of transplant vascular disease. Recent studies from our group and others have shed light on the mechanisms of endothelial dysfunction and its importance in cardiac allograft vasculopathy. In addition, the alteration in endothelial function contributes to vascular inflammation and progression of the disease.

Animals↗

Nicotine promotes arteriogenesis.

OBJECTIVES: In the current study, we used a model of limb ischemia to determine whether nicotine could enhance arteriogenesis, to compare the magnitude of this effect to the angiogenic factor basic fibroblast growth factor (bFGF), and to investigate the mechanisms of the effect. BACKGROUND: We have shown previously that nicotine stimulates angiogenesis via stimulation of endothelial nicotinic cholinergic receptors. Stimulation of endothelial nicotinic cholinergic receptors causes endothelial cell proliferation, migration, and formation of capillary networks in vitro and angiogenesis in vivo in conditions of ischemia and inflammation. METHODS: New Zealand White rabbits (n = 85) underwent unilateral femoral artery occlusion and were randomized to nicotine (0.05 to 5.0 microg/kg/day), bFGF (10 microg/kg/day), or vehicle delivered intra-arterially via osmotic minipumps. At day 21, morphologic changes were assessed by immunohistochemistry and angiography. Blood flow in the ischemic limb was determined by intra-arterial Doppler flow measurements and microsphere distribution. RESULTS: Nicotine enhanced capillary density in the ischemic hind-limb to a similar extent as bFGF. Nicotine also increased angiographic score, calf blood pressure ratio, intra-arterial Doppler flow, and microsphere distribution. In vitro, nicotine stimulated monocyte adhesion and transmigration. Nicotine increased by two- to three-fold the expression of monocyte adhesion molecules CD11b and CD11a; the expression of the endothelial adhesion molecule intercellular adhesion molecule-1; and the endothelial release of monocyte chemoattractant protein-1. CONCLUSIONS: In the short term, nicotine promotes angiogenesis and arteriogenesis in the setting of ischemia. The effect of nicotine may be mediated in part by activation of endothelial-monocyte interactions involved in arteriogenesis.

Angiogenesis Inducing Agents↗

Endothelial determinants of dendritic cell adhesion and migration: new implications for vascular diseases.

OBJECTIVE: Atherosclerosis is a chronic disease triggered by endothelial injury and sustained by inflammation. Dendritic cells (DCs) are critical for the cell-mediated arm of an immune response and are known to influence inflammatory immunity. A fundamental aspect of DC function is their capacity to adhere and migrate through vascular endothelial cells (ECs). We investigated the role of endothelial activation and dysregulation of the NO pathway on DC adhesion and migration. METHODS AND RESULTS: We discovered that DC adhesion and migration are modulated by changes in endothelial function. DC adhesion and transmigration were markedly increased after exposing ECs to hypoxia, oxidized low density lipoprotein, or tumor necrosis factor-alpha. Specifically, inhibition of endothelial NO synthase increased DC binding and transmigration. L-Arginine or 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibition partially decreased DC-EC interaction. CONCLUSIONS: The results of this study suggest that the adhesion and migration of DCs are increased by stimuli known to accelerate atherogenesis. Vice versa, augmentation of endothelial NO synthase activity prevents DC adhesion. These findings may provide insight into the inflammatory processes occurring in atherosclerosis. Because DCs control immunity, regulating DC-EC interaction may be relevant to inflammation and atherogenesis.

Aorta↗

Statins have biphasic effects on angiogenesis.

BACKGROUND: Statins inhibit HMG-CoA reductase to reduce the synthesis of cholesterol and isoprenoids that modulate diverse cell functions. We investigated the effect of the statins cerivastatin and atorvastatin on angiogenesis in vitro and in vivo. METHODS AND RESULTS: Endothelial cell proliferation, migration, and differentiation were enhanced at low concentrations (0.005 to 0.01 micromol/L) but significantly inhibited at high statin concentrations (0.05 to 1 micromol/L). Antiangiogenic effects at high concentrations were associated with decreased endothelial release of vascular endothelial growth factor and increased endothelial apoptosis and were reversed by geranylgeranyl pyrophosphate. In murine models, inflammation-induced angiogenesis was enhanced with low-dose statin therapy (0.5 mg x kg(-1) x d(-1)) but significantly inhibited with high concentrations of cerivastatin or atorvastatin (2.5 mg x kg(-1) x d(-1)). Despite the fact that high-dose statin treatment was effective at reducing lipid levels in hyperlipidemic apolipoprotein E-deficient mice, it impaired rather than enhanced angiogenesis. Finally, high-dose cerivastatin decreased tumor growth and tumor vascularization in a murine Lewis lung cancer model. CONCLUSIONS: HMG-CoA reductase inhibition has a biphasic dose-dependent effect on angiogenesis that is lipid independent and associated with alterations in endothelial apoptosis and vascular endothelial growth factor signaling. Statins have proangiogenic effects at low therapeutic concentrations but angiostatic effects at high concentrations that are reversed by geranylgeranyl pyrophosphate. At clinically relevant doses, statins may modulate angiogenesis in humans via effects on geranylated proteins.

Animals↗