|
1
|
Attachaipanich T, Chattipakorn SC, Chattipakorn N. Cardiovascular toxicities by calcineurin inhibitors: Cellular mechanisms behind clinical manifestations. Acta Physiol (Oxf) 2024; 240:e14199. [PMID: 38984711 DOI: 10.1111/apha.14199] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2024] [Revised: 06/19/2024] [Accepted: 06/25/2024] [Indexed: 07/11/2024]
Abstract
Calcineurin inhibitors (CNI), including cyclosporine A (CsA) and tacrolimus (TAC), are cornerstones of immunosuppressive therapy in solid organ transplant recipients. While extensively recognized for their capacity to induce nephrotoxicity, hypertension, and dyslipidemia, emerging reports suggest potential direct cardiovascular toxicities associated with CNI. Evidence from both in vitro and in vivo studies has demonstrated direct cardiotoxic impact of CNI, manifesting itself as induction of cardiomyocyte apoptosis, enhanced oxidative stress, inflammatory cell infiltration, and cardiac fibrosis. CNI enhances cellular apoptosis through CaSR via activation of the p38 MAPK pathway and deactivation of the ERK pathway, and enhancement of miR-377 axis. Although CNI could attenuate cardiac hypertrophy in certain animal models, CNI concurrently impaired systolic function, enhanced cardiac fibrosis, and increased the risk of heart failure. Evidence from in vivo studies demonstrated that CNI prolong the duration of action potentials through a decrease in potassium current. CNI also exerted direct effects on endothelial cell injury, inducing apoptosis and enhancing oxidative stress. CNI may induce vascular inflammation through TLR4 via MyD88 and TRIF pathways. In addition, CNI affects vascular function by impairing endothelial-dependent vasodilation and promoting vasoconstriction. Clinical studies in transplant patients also revealed an increased incidence of cardiac remodeling. However, the evidence is constrained by the limited number of participants and potential confounding factors. Several studies indicate differing cardiovascular toxicity profiles between CsA and TAC, and these could be potentially due to their different interactions with calcineurin subunits and calcineurin-independent effects. Further studies are needed to clarify these mechanisms to improve cardiovascular outcomes for transplant patients with CNI.
Collapse
Affiliation(s)
- Tanawat Attachaipanich
- Cardiac Electrophysiology Research and Training Center, Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand
- Center of Excellence in Cardiac Electrophysiology Research, Chiang Mai University, Chiang Mai, Thailand
| | - Siriporn C Chattipakorn
- Cardiac Electrophysiology Research and Training Center, Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand
- Center of Excellence in Cardiac Electrophysiology Research, Chiang Mai University, Chiang Mai, Thailand
| | - Nipon Chattipakorn
- Cardiac Electrophysiology Research and Training Center, Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand
- Center of Excellence in Cardiac Electrophysiology Research, Chiang Mai University, Chiang Mai, Thailand
- Cardiac Electrophysiology Research Unit, Department of Physiology, Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand
| |
Collapse
|
|
2
|
Molaei E, Molaei A, Dashti-Khavidaki S, Nasiri-Toosi M, Abbasi MR, Jafarian A. Could the administration of SGLT2i agents serve as a viable prophylactic approach against CNI-induced toxicities? Med Hypotheses 2024; 189:111417. [DOI: 10.1016/j.mehy.2024.111417] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
|
|
3
|
Cuomo G, Cioffi G, Di Lorenzo A, Iannone FP, Cudemo G, Iannicelli AM, Pacileo M, D’Andrea A, Vigorito C, Iannuzzo G, Giallauria F. Proprotein Convertase Subtilisin/Kexin Type 9 Inhibitors Use for Atherogenic Dyslipidemia in Solid Organ Transplant Patients. J Clin Med 2022; 11:3247. [PMID: 35683632 PMCID: PMC9180971 DOI: 10.3390/jcm11113247] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2022] [Revised: 06/03/2022] [Accepted: 06/04/2022] [Indexed: 01/27/2023] Open
Abstract
Dyslipidemia is a widespread risk factor in solid organ transplant patients, due to many reasons, such as the use of immunosuppressive drugs, with a consequent increase in cardiovascular diseases in this population. PCSK9 is an enzyme mainly known for its role in altering LDL levels, consequently increasing cardiovascular risk. Monoclonal antibody PCSK9 inhibitors demonstrated remarkable efficacy in the general population in reducing LDL cholesterol levels and preventing cardiovascular disease. In transplant patients, these drugs are still poorly used, despite having comparable efficacy to the general population and giving fewer drug interactions with immunosuppressants. Furthermore, there is enough evidence that PCSK9 also plays a role in other pathways, such as inflammation, which is particularly dangerous for graft survival. In this review, the current evidence on the function of PCSK9 and the use of its inhibitors will be discussed, particularly in transplant patients, in which they may provide additional benefits.
Collapse
Affiliation(s)
- Gianluigi Cuomo
- Department of Translational Medical Sciences, “Federico II” University of Naples, Via S. Pansini 5, 80131 Naples, Italy; (G.C.); (G.C.); (A.D.L.); (G.C.); (A.M.I.); (C.V.)
| | - Giuseppe Cioffi
- Department of Translational Medical Sciences, “Federico II” University of Naples, Via S. Pansini 5, 80131 Naples, Italy; (G.C.); (G.C.); (A.D.L.); (G.C.); (A.M.I.); (C.V.)
| | - Anna Di Lorenzo
- Department of Translational Medical Sciences, “Federico II” University of Naples, Via S. Pansini 5, 80131 Naples, Italy; (G.C.); (G.C.); (A.D.L.); (G.C.); (A.M.I.); (C.V.)
| | - Francesca Paola Iannone
- Department of Clinical Medicine and Surgery, “Federico II” University of Naples, Via S. Pansini 5, 80131 Naples, Italy; (F.P.I.); (G.I.)
| | - Giuseppe Cudemo
- Department of Translational Medical Sciences, “Federico II” University of Naples, Via S. Pansini 5, 80131 Naples, Italy; (G.C.); (G.C.); (A.D.L.); (G.C.); (A.M.I.); (C.V.)
| | - Anna Maria Iannicelli
- Department of Translational Medical Sciences, “Federico II” University of Naples, Via S. Pansini 5, 80131 Naples, Italy; (G.C.); (G.C.); (A.D.L.); (G.C.); (A.M.I.); (C.V.)
| | - Mario Pacileo
- Unit of Cardiology and Intensive Care, Umberto I Hospital, 84014 Nocera Inferiore, Italy; (M.P.); (A.D.)
| | - Antonello D’Andrea
- Unit of Cardiology and Intensive Care, Umberto I Hospital, 84014 Nocera Inferiore, Italy; (M.P.); (A.D.)
| | - Carlo Vigorito
- Department of Translational Medical Sciences, “Federico II” University of Naples, Via S. Pansini 5, 80131 Naples, Italy; (G.C.); (G.C.); (A.D.L.); (G.C.); (A.M.I.); (C.V.)
| | - Gabriella Iannuzzo
- Department of Clinical Medicine and Surgery, “Federico II” University of Naples, Via S. Pansini 5, 80131 Naples, Italy; (F.P.I.); (G.I.)
| | - Francesco Giallauria
- Department of Translational Medical Sciences, “Federico II” University of Naples, Via S. Pansini 5, 80131 Naples, Italy; (G.C.); (G.C.); (A.D.L.); (G.C.); (A.M.I.); (C.V.)
| |
Collapse
|
|
4
|
Milone G, Bellofiore C, Leotta S, Milone GA, Cupri A, Duminuco A, Garibaldi B, Palumbo G. Endothelial Dysfunction after Hematopoietic Stem Cell Transplantation: A Review Based on Physiopathology. J Clin Med 2022; 11:jcm11030623. [PMID: 35160072 PMCID: PMC8837122 DOI: 10.3390/jcm11030623] [Citation(s) in RCA: 30] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2021] [Revised: 01/19/2022] [Accepted: 01/23/2022] [Indexed: 12/12/2022] Open
Abstract
Endothelial dysfunction (ED) is frequently encountered in transplant medicine. ED is an argument of high complexity, and its understanding requires a wide spectrum of knowledge based on many fields of basic sciences such as molecular biology, immunology, and pathology. After hematopoietic stem cell transplantation (HSCT), ED participates in the pathogenesis of various complications such as sinusoidal obstruction syndrome/veno-occlusive disease (SOS/VOD), graft-versus-host disease (GVHD), transplant-associated thrombotic microangiopathy (TA-TMA), idiopathic pneumonia syndrome (IPS), capillary leak syndrome (CLS), and engraftment syndrome (ES). In the first part of the present manuscript, we briefly review some biological aspects of factors involved in ED: adhesion molecules, cytokines, Toll-like receptors, complement, angiopoietin-1, angiopoietin-2, thrombomodulin, high-mobility group B-1 protein, nitric oxide, glycocalyx, coagulation cascade. In the second part, we review the abnormalities of these factors found in the ED complications associated with HSCT. In the third part, a review of agents used in the treatment of ED after HSCT is presented.
Collapse
|
|
5
|
Payne GA, Hage FG, Acharya D. Transplant allograft vasculopathy: Role of multimodality imaging in surveillance and diagnosis. J Nucl Cardiol 2016; 23:713-27. [PMID: 26711101 DOI: 10.1007/s12350-015-0373-3] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2015] [Accepted: 11/27/2015] [Indexed: 01/22/2023]
Abstract
Cardiac allograft vasculopathy (CAV) is a challenging long-term complication of cardiac transplantation and remains a leading long-term cause of graft failure, re-transplantation, and death. CAV is an inflammatory vasculopathy distinct from traditional atherosclerotic coronary artery disease. Historically, the surveillance and diagnosis of CAV has been dependent on serial invasive coronary angiography with intravascular imaging. Although commonly practiced, angiography is not without significant limitations. Technological advances have provided sophisticated imaging techniques for CAV assessment. It is now possible to assess the vascular lumen, vessel wall characteristics, absolute blood flow, perfusion reserve, myocardial contractile function, and myocardial metabolism and injury in a noninvasive, expeditious manner with little risk. The current article will review key imaging modalities for the surveillance, diagnosis, and prognosis of CAV and discuss coronary physiology of transplanted hearts with emphasis on the clinical implications for provocative and vasodilator stress testing.
Collapse
Affiliation(s)
- Gregory A Payne
- Division of Cardiovascular Disease, University of Alabama at Birmingham School of Medicine, Tinsley Harrison Tower, Room 321, Birmingham, AL, 35294-006, USA
| | - Fadi G Hage
- Division of Cardiovascular Disease, University of Alabama at Birmingham School of Medicine, Tinsley Harrison Tower, Room 321, Birmingham, AL, 35294-006, USA
- Section of Cardiology, Birmingham Veterans Affairs Medical Center, Birmingham, AL, USA
| | - Deepak Acharya
- Division of Cardiovascular Disease, University of Alabama at Birmingham School of Medicine, Tinsley Harrison Tower, Room 321, Birmingham, AL, 35294-006, USA.
| |
Collapse
|
|
6
|
Vecchiati A, Tellatin S, Angelini A, Iliceto S, Tona F. Coronary microvasculopathy in heart transplantation: Consequences and therapeutic implications. World J Transplant 2014; 4:93-101. [PMID: 25032098 PMCID: PMC4094955 DOI: 10.5500/wjt.v4.i2.93] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/26/2013] [Revised: 01/11/2014] [Accepted: 03/12/2014] [Indexed: 02/05/2023] Open
Abstract
Despite the progress made in the prevention and treatment of rejection of the transplanted heart, cardiac allograft vasculopathy (CAV) remains the main cause of death in late survival transplanted patients. CAV consists of a progressive diffuse intimal hyperplasia and the proliferation of vascular smooth muscle cells, ending in wall thickening of epicardial vessels, intramyocardial arteries (50-20 μm), arterioles (20-10 μm), and capillaries (< 10 μm). The etiology of CAV remains unclear; both immunologic and non-immunologic mechanisms contribute to endothelial damage with a sustained inflammatory response. The immunological factors involved are Human Leukocyte Antigen compatibility between donor and recipient, alloreactive T cells and the humoral immune system. The non-immunological factors are older donor age, ischemia-reperfusion time, hyperlipidemia and CMV infections. Diagnostic techniques that are able to assess microvascular function are lacking. Intravascular ultrasound and fractional flow reserve, when performed during coronary angiography, are able to detect epicardial coronary artery disease but are not sensitive enough to assess microvascular changes. Some authors have proposed an index of microcirculatory resistance during maximal hyperemia, which is calculated by dividing pressure by flow (distal pressure multiplied by the hyperemic mean transit time). Non-invasive methods to assess coronary physiology are stress echocardiography, coronary flow reserve by transthoracic Doppler echocardiography, single photon emission computed tomography, and perfusion cardiac magnetic resonance. In this review, we intend to analyze the mechanisms, consequences and therapeutic implications of microvascular dysfunction, including an extended citation of relevant literature data.
Collapse
|
|
7
|
Som R, Morris PJ, Knight SR. Graft Vessel Disease Following Heart Transplantation: A Systematic Review of the Role of Statin Therapy. World J Surg 2014; 38:2324-34. [DOI: 10.1007/s00268-014-2543-x] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
|
|
8
|
Gökceoğlu AU, Akman S, Köksoy S, Şahin E, Koyun M, Çomak E, Doğan ÇS, Akbaş H, Dinçkan A. Circulating endothelial cells in pediatric renal transplant recipients. Pediatr Nephrol 2013; 28:2377-82. [PMID: 24018796 DOI: 10.1007/s00467-013-2588-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/16/2013] [Revised: 07/15/2013] [Accepted: 07/23/2013] [Indexed: 11/26/2022]
Abstract
BACKGROUND An increase in the number of circulating endothelial cells (CEC) indicates endothelial damage and the risk of cardiovascular disease. The aim of our study was to investigate the association of CEC with various clinical parameters in pediatric renal transplant recipients. METHODS CEC, defined as CD45(-)CD146(+), were enumerated by flow cytometry from the peripheral blood of 50 pediatric renal transplant recipients and 20 healthy controls. Clinical parameters, including renal function tests, fasting blood glucose, serum cholesterol and triglyceride, cyclosporine A (CsA) (trough and 2nd-hour) and tacrolimus (tac) trough blood levels and their association with CEC numbers were analyzed. RESULTS CEC numbers of patients were higher than those of controls (respectively, 128 ± 89 cells/ml (42-468 cells/ml), 82 ± 33 cells/ml (32-137 cells/ml), p = 0.024). There was a statistically significant negative correlation between CEC numbers and glomerular filtration rate (GFR) (r = -0.300, p = 0.012). There was also a statistically positive association between CEC numbers and transplant duration as well as cyclosporine trough level (respectively, r = 0.397, p = 0.004, r = 0.714, p = 0.004). CEC numbers in patients on tac and CsA were similar (p = 0.716). CONCLUSIONS Our results demonstrate that renal transplant recipients with high CsA trough blood level, longer transplant duration, and lower GFR, are at greater risk of developing endothelial damage.
Collapse
Affiliation(s)
- Arife Uslu Gökceoğlu
- Department of Pediatric Nephrology, Akdeniz University Medical Faculty, Antalya, Turkey,
| | | | | | | | | | | | | | | | | |
Collapse
|
|
9
|
Gutiérrez E, Flammer AJ, Lerman LO, Elízaga J, Lerman A, Fernández-Avilés F. Endothelial dysfunction over the course of coronary artery disease. Eur Heart J 2013; 34:3175-81. [PMID: 24014385 DOI: 10.1093/eurheartj/eht351] [Citation(s) in RCA: 231] [Impact Index Per Article: 19.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Abstract
The vascular endothelium regulates blood flow in response to physiological needs. Endothelial dysfunction is closely related to atherosclerosis and its risk factors, and it constitutes an intermediate step on the progression to adverse events throughout the natural history of coronary artery disease (CAD), often affecting clinical outcomes. Understanding the relation of endothelial function with CAD provides an important pathophysiological insight, which can be useful both in clinical and research management. In this review, we summarize the current knowledge on endothelial dysfunction and its prognostic influence throughout the natural history of CAD, from early atherosclerosis to post-transplant management.
Collapse
Affiliation(s)
- Enrique Gutiérrez
- Servicio de Cardiología, Instituto de Investigación Sanitaria, Hospital General Universitario Gregorio Marañón, Madrid, Spain
| | | | | | | | | | | |
Collapse
|
|
10
|
Neither cyclosporine nor tacrolimus deteriorate endothelial function in renal transplant recipients assessed with reactive hyperernia index. Transplant Proc 2013; 45:1567-70. [PMID: 23726621 DOI: 10.1016/j.transproceed.2012.12.020] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2012] [Revised: 11/18/2012] [Accepted: 12/04/2012] [Indexed: 12/31/2022]
Abstract
BACKGROUND Cardiovascular mortality in renal transplant recipients is nearer 10-fold higher than in general population. Immunosuppressive therapy is one possible cause, for these drugs can modify cardiovascular risk factors, which can induce endothelial dysfunction, the first step in the process of atherosclerosis. The aim of this study was to compare vasodilatatory function of endothelium in renal transplant recipients in relation to the immunosuppressive drug-cyclosporine or tacrolimus. MATERIALS AND METHODS We examined 40 patients at 48.9 ± 36 months post-renal transplantation: 22 taking tacrolimus (group 1) and 18 taking cyclosporine (group 2). The renal transplant recipients were compared with a control group of 18 healthy people. Endothelial function was assessed by peripheral arterial tonometry (PAT) using the EndoPAT 2000 device to measure RHI (reactive hyperemia index) and AI% (augmentation index%). RESULTS The overall median values of RHI were higher than the value accepted as a normal (1.67). The RHI median value in group 1 was 2.00 (quartile 1: 1.66; quartile 2: 2.72), not different from that in group 2 [1.90 (quartile 1: 1.56; quartile 2: 2.17)] or the controls [2.11 (quartile 1: 1.77; quartile 2: 2.50)]. Multivariate analysis revealed age to be the independent factor influencing RHI in all examined groups but treatment with calcium channel blockers appeared to be the only independent factor influencing RHI among renal transplant recipients. AI% values were not significantly different between the 2 groups of renal transplant recipients, but it was significantly higher among the controls than among subjects treated with tacrolimus. CONCLUSIONS Vasodilatatory function of endothelium assessed by PAT in renal transplant recipients was not worse than in healthy people. It was not different between cyclosporine or tacrolimus. Arterial stiffness measured as AI% depend on age but not the calcineurin inhibitor, which showed little effect.
Collapse
|
|
11
|
Comparative In VitroEffects of Calcineurin Inhibitors on Functional Vascular Relaxations of Both Rat Thoracic and Abdominal Aorta. Adv Pharmacol Sci 2013; 2013:718313. [PMID: 23853606 PMCID: PMC3703371 DOI: 10.1155/2013/718313] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/17/2013] [Accepted: 06/02/2013] [Indexed: 11/18/2022] Open
Abstract
Background and Aim. Calcineurin inhibitors (CNIs) have shown to develop hypertension in transplant patients. The in vitro incubation effects of cyclosporine (CsA) and tacrolimus (Tac) on vascular relaxations of rat thoracic aorta (TA) and abdominal aorta (AA) need to be investigated.
Methods. The optimal concentrations of CsA (1.0 mg/mL) and Tac (0.1 mg/mL) used to compare endothelium-dependent (acetylcholine (ACh)) and endothelium-independent (sodium nitroprusside (SNP)) vascular relaxation against the agonists in phenylephrine (PE-) constricted TA and AA of 13-week-old male Sprague Dawley rats (n = 6).
Results. In TA, the maximal vasodilator response elicited by ACh (control: Imax 98%) was significantly (P < 0.01) inhibited by CsA (Imax 10%) but not by Tac (Imax 97%). In AA, (control: IC50 50 nM; Imax 100%) CsA (IC50 7 μM; (P < 0.01) showed strong sensitivity to inhibit ACh-dependent vascular relaxation than Tac (IC50 215 nM (P < 0.05); Imax 98%). CsA and Tac failed to affect the inhibitory responses to SNP in both TA and AA.
Conclusion. CsA exerts profound inhibitory effect on endothelium-dependent vasodilatation as compared to Tac in both TA and AA. Aortic rings from the thoracic region are more sensitive to CNIs, since the vasodilator response to ACh is solely mediated by NO while in the AA, ACh likely recruits other endothelial mediators besides NO to maintain vasodilatation.
Collapse
|
|
12
|
|
|
13
|
Karlsson LO, Bergh N, Grip L. Cyclosporine A, 2.5 mg/kg, does not reduce myocardial infarct size in a porcine model of ischemia and reperfusion. J Cardiovasc Pharmacol Ther 2011; 17:159-63. [PMID: 21572075 DOI: 10.1177/1074248411407636] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/15/2022]
Abstract
BACKGROUND In recent years, cyclosporine A (CsA) has emerged as a promising therapy to limit myocardial ischemic-reperfusion injury, presumably by inhibiting the opening of the mitochondrial permeability transition pore. Results from different large animal models are conflicting, however, with failure to prove beneficial effects of 10 mg/kg CsA administered at reperfusion. Recently, a small clinical study using a bolus of 2.5 mg/kg CsA showed promising but not unequivocal results. The aim of the present study was to estimate the magnitude of a possible infarct reduction with the use of the latter regimen in a closed-chest porcine model for ischemia and reperfusion. Materials and METHODS Pigs underwent catheterization with balloon occlusion of the left descending coronary artery for 40 minutes, followed by reperfusion for 4 hours. They were randomized to receive an intravenous bolus 7 minutes before reperfusion of either 2.5 mg/kg CsA (n = 12) or saline (control, n = 11). Hearts were stained to quantify area at risk and infarct size. RESULTS Throughout the experiment, there were no differences between the groups in baseline characteristics or hemodynamic variables. CsA treatment did not reduce infarct size as a proportion of area at risk compared with control (51% ± 6% and 54% ± 6%, respectively, P = .75). CONCLUSION In a closed-chest porcine model for myocardial ischemia and reperfusion injury, 2.5 mg/kg CsA administered before reperfusion did not reduce infarct size.
Collapse
Affiliation(s)
- Lars O Karlsson
- Department of Molecular and Clinical Medicine, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
| | | | | |
Collapse
|
|
14
|
Zhang M, Wu Q, Shui C. All-trans retinoic acid attenuates cardiac allograft vasculopathy in rats. Transplant Proc 2010; 42:1895-8. [PMID: 20620545 DOI: 10.1016/j.transproceed.2010.02.094] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/13/2009] [Revised: 01/15/2010] [Accepted: 02/26/2010] [Indexed: 11/26/2022]
Abstract
OBJECTIVE We sought to study the inhibitory effects of all-trans retinoic acid (ATRA) on cardiac allograft vasculopathy in rats. METHODS Inbred Wistar and Sprague-Dawley rats were used as donors and recipients, respectively. After abdominal heterotopic heart transplantation, animals were randomized to a cyclosporine (CsA) group versus a CsA+ATRA group: 10 mg/kg/d CsA versus the same CsA dose plus 10 mg/kg/d ATRA. Transplanted hearts were analyzed at 60 days. Cardiac allograft sections were treated with Van Giesson stain to examine vascular luminal occlusion, with immunohistochemistry for CD68 and proliferating cell nuclear antigen (PCNA), and with reverse-transcription polymerase chain reaction (RT-PCR) for platelet-derived growth factor A (PDGF-A) mRNA. RESULTS Luminal occlusion in the CsA+ATRA group was significantly less than that in the CsA group (40.10 +/- 8.20% vs 62.86 +/- 17.18%; P < .01). The CsA+ATRA group showed a marked reduction in PCNA- and CD68-positive cells: namely, 33.96 +/- 8.65% versus 60.17 +/- 17.74% (P < .01) and 17.63 +/- 4.24% versus 32.13 +/- 9.26 (P < .01), respectively. RT-PCR analysis showed that relative PDGF-A mRNA content in the CsA+ATRA group was significantly decreased compared with the CsA group (0.46 +/- 0.08 vs 0.94 +/- 0.11; P < .01). CONCLUSION ATRA may attenuate rat cardiac allograft vasculopathy by inhibiting macrophage infiltration and cell proliferation.
Collapse
Affiliation(s)
- M Zhang
- Department of Cardiovascular Surgery, First Hospital of Tsinghua University, Beijing, China.
| | | | | |
Collapse
|
|
15
|
Lie RH, Stoettrup N, Sloth E, Hasenkam JM, Kroyer R, Nielsen TT. Post-conditioning with cyclosporine A fails to reduce the infarct size in an in vivo porcine model. Acta Anaesthesiol Scand 2010; 54:804-13. [PMID: 20455870 DOI: 10.1111/j.1399-6576.2010.02241.x] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022]
Abstract
BACKGROUND Cyclosporine A has generated intense interest in the field of cardioprotection due to its ability to protect the mitochondria at reperfusion by blocking the opening of the mitochondrial permeability transition pore. The aim of our study was to examine the cardioprotective effect of Sandimmun, a clinically available formulation of cyclosporine A, in an in vivo large mammal model. METHODS Forty-eight pigs were randomly allocated to one of three groups: (i) Control group (Con, n=19), (ii) Cyclosporine group, (Cyclo, n=19) Sandimmun 10 mg/kg i.v. bolus 5 min before reperfusion and (iii) Pre-conditioning group (Precon, n=10) two cycles of 10 min ischemia interspersed with 30-min reperfusion. The study was further sub-divided into a metabolic protocol, evaluating myocardial metabolism by measuring changes in the interstitial lactate concentration, and a coronary flow protocol. All animals were subjected to 40 min of left anterior descending coronary artery occlusion, followed by 180 min of reperfusion before histochemical staining and assessment of infarct size by planimetry. RESULTS Infarct sizes were measured as: Con 51.4 +/- 16.5%, Cyclo 47.3 +/- 15.7% and Precon 2.4 +/- 3.6%, with no significant difference between the Con and Cyclo groups but a highly significant difference between the Precon and Cyclo and Con groups (P<0.0001 for both comparisons). In the Cyclo group, the interstitial lactate concentration was significantly increased compared with the Con group at 6-min reperfusion, although significantly lower at 14 min presumably due to accelerated washout. CONCLUSION In this large animal model, a 10 mg/kg bolus administration of Sandimmun 5 min before reperfusion did not reduce the infarct size.
Collapse
Affiliation(s)
- R H Lie
- Department of Anaesthesiology and Intensive Care, Aarhus University Hospital, Aarhus, Denmark.
| | | | | | | | | | | |
Collapse
|
|
16
|
|
|
17
|
Raichlin E, Prasad A, Kremers WK, Edwards BS, Rihal CS, Lerman A, Kushwaha SS. Sirolimus as primary immunosuppression is associated with improved coronary vasomotor function compared with calcineurin inhibitors in stable cardiac transplant recipients. Eur Heart J 2009; 30:1356-63. [PMID: 19383734 DOI: 10.1093/eurheartj/ehp123] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/02/2023] Open
Abstract
AIMS The aim of this study was to evaluate coronary vasomotor function in cardiac transplant recipients maintained on sirolimus (SRL)- or cyclosporin (CyA)-based immunosuppression. METHODS AND RESULTS Endothelium-independent response to intracoronary nitroglycerin and adenosine and endothelium-dependent response to intracoronary acetylcholine (Ach) were assessed in 15 SRL- and 21 CyA- treated subjects with angiographically normal coronary arteries. Baseline mean blood pressure was lower in the SRL group (85.6 +/- 10.3 vs. 105.2 +/- 8.7 mmHg, P = 0.002). There was no difference between the groups in coronary flow reserve after adenosine administration in multivariable analysis (P = 0.34). Nitroglycerin administration resulted in increase in coronary artery diameter in the SRL compared with the CyA groups (2.79 +/- 0.54 vs. 2.57 +/- 0.61, P = 0.0036). In 13 SRL-treated subjects without evidence of cardiac allograft vasculopathy (CAV), Ach administration resulted in less epicardial vasoconstriction compared with CyA-treated subjects (2.7 +/- 17.7 vs. -15.6 +/- 17.2%, P = 0.005). Two SRL-treated subjects with three-dimensional intravascular ultrasound evidence of CAV developed coronary spasm in response to Ach 10(-4). Microvascular endothelial function did not differ between the groups. CONCLUSION Sirolimus immunosuppression is associated with less pronounced coronary epicardial endothelial dysfunction compared with CyA immunosuppression. Improvement of coronary vasomotor function with SRL may be an important mechanism for the prevention of CAV.
Collapse
Affiliation(s)
- Eugenia Raichlin
- William J. von Liebig Transplant Center and the Division of Cardiovascular Diseases, Mayo Clinic (Go 5-469), 200 First Street, SW, Rochester, MN 55905, USA
| | | | | | | | | | | | | |
Collapse
|
|
18
|
Artifoni L, Benetti E, Centi S, Negrisolo S, Ghiggeri GM, Ginevri F, Ghio L, Edefonti A, Brambilla C, Cagni N, Murer L. The impact of eNOS, MTR and MTHFR polymorphisms on renal graft survival in children and young adults. Nephrol Dial Transplant 2009; 24:2931-7. [PMID: 19349296 DOI: 10.1093/ndt/gfp161] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/14/2022] Open
Abstract
BACKGROUND The main cause of reduced long-term graft survival is chronic allograft injury. Cardiovascular risk factors such as hyperhomocysteinaemia, accumulation of asymmetric dimethylarginine, increased oxidative stress and decreased production of nitric oxide seem to play an important role. Functional polymorphisms of the endothelial isoform of nitric oxide synthase (NOS) gene cause an alteration in nitric oxide production. Nitric oxide levels, and thus oxidative stress, are also influenced by hyperhomocysteinaemia. METHODS We carried out a genetic analysis of endothelial nitric oxide synthase (eNOS) 894G>T, methionine synthase (MTR) 2756A>G and methylenetetrahydrofolate reductase (MTHFR) 677C>T/1298A>C in 268 renal allograft recipient/donor (D/R) matches, with respect to long-term graft survival. RESULTS While MTHFR 677C>T/1298A>G and MTR 2756A>G polymorphism distribution in both recipients (R) and donors (D) showed no significant difference between matches with loss of graft function and those with long-term graft survival, the frequency of the eNOS 894TT genotype of donors was significantly increased (P = 0.040) in matches with better graft survival. The multivariate analysis identified the eNOS 894 genotype and clinically acute rejection episodes as independent risk factors for graft loss (P = 0.0406 and P = 0.0093, respectively). CONCLUSIONS The association between eNOS 894G>T polymorphism of donors and graft survival seems to suggest a role for this gene in chronic allograft injury; however, further studies are needed to confirm this hypothesis.
Collapse
Affiliation(s)
- Lina Artifoni
- Department of Paediatrics, University of Padua, Italy.
| | | | | | | | | | | | | | | | | | | | | |
Collapse
|
|
19
|
Dual immunosuppression enhances vasomotor injury: Interactive effect between endothelin-1 and nitric oxide bioavailability. J Thorac Cardiovasc Surg 2008; 135:938-44. [DOI: 10.1016/j.jtcvs.2007.09.075] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/14/2007] [Revised: 08/18/2007] [Accepted: 09/06/2007] [Indexed: 11/24/2022]
|
|
20
|
Korkmaz C. Potential effects of cyclosporin A on coronary vasomotor function in young patients with systemic lupus erythematosus: comment on the article by Hirata et al. ARTHRITIS AND RHEUMATISM 2008; 58:330-331. [PMID: 18163479 DOI: 10.1002/art.23234] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/25/2023]
|
|
21
|
Perrault LP, Aubin MC, Malo O, Thollon C, Villeneuve N, Vilaine JP, Vanhoutte PM. Status of the endothelium-derived hyperpolarizing factor pathway in coronary arteries after heterotopic heart transplantation. J Heart Lung Transplant 2007; 26:48-55. [PMID: 17234517 DOI: 10.1016/j.healun.2006.10.015] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2006] [Revised: 09/13/2006] [Accepted: 10/19/2006] [Indexed: 10/23/2022] Open
Abstract
BACKGROUND After the first year of transplantation, the major limitation to long-term survival is the development of graft coronary vasculopathy, characterized by a pathologic activation of the endothelium with an attendant loss of its regulatory properties on homeostasis of the vascular wall. The present study was designed to evaluate the integrity of coronary vascular relaxations attributed to the endothelium-derived hyperpolarizing factor (EDHF) and to study hyperpolarization of smooth muscle cells after heterotopic heart transplantation. METHODS Six weeks after heart transplantation in a porcine model, vascular reactivity studies of control, native and allograft epicardial coronary artery rings were performed in standard organ chamber experiments. Moreover, membrane potential measurements were made with intracellular microelectrodes in rings of native and allograft coronary arteries. RESULTS There was a significant decrease in endothelium-dependent relaxations to 5-hydroxytryptamine (5-HT), high doses of bradykinin (BK) alone and BK plus N-omega-nitro-L-arginine (L-NNA) in rings from allograft compared to native, whereas the variation was significantly increased in response to cromakalim, a K(+)-ATP channel opener. Electrical and mechanical recordings showed no alteration in the resting membrane potential of smooth muscle cells, depolarization during contraction to prostaglandin F(2alpha) (PGF(2alpha)), or hyperpolarization in the presence of BK + L-NNA in rings of allograft vs native. CONCLUSIONS In this swine model of heart transplantation, part of the reduction in endothelium-dependent relaxations to BK may be attributed to an alteration in the activity of EDHF. This impairment of EDHF-mediated relaxations may compound the endothelial dysfunction preceding the development of coronary graft vasculopathy.
Collapse
Affiliation(s)
- Louis P Perrault
- Research Center, Montreal Heart Institute, Montreal, Quebec, Canada.
| | | | | | | | | | | | | |
Collapse
|
|
22
|
Erdbruegger U, Haubitz M, Woywodt A. Circulating endothelial cells: a novel marker of endothelial damage. Clin Chim Acta 2006; 373:17-26. [PMID: 16836991 DOI: 10.1016/j.cca.2006.05.016] [Citation(s) in RCA: 98] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2006] [Revised: 05/03/2006] [Accepted: 05/04/2006] [Indexed: 12/28/2022]
Abstract
Circulating endothelial cells (CECs) were first described over 30 years ago in smears of peripheral blood. Since then, more sophisticated techniques for CEC isolation have become available. In particular, immunomagnetic isolation and fluorescence-activated cell sorting (FACS) have been employed with success. We provide a short historical perspective and a comprehensive review on the subject. We review isolation and enumeration of CECs with an emphasis on CD146-driven immunomagnetic isolation and FACS. We describe, in great detail, advantages and pitfalls of both approaches and compare their specificity. Moreover, we provide a comprehensive list of clinical studies in this field and describe the possible clinical use of CECs. We also describe the phenotype of these cells and list typical surface markers. In addition, we review the phenotype of CECs and discuss mechanisms of detachment. We speculate about potential interactions between CECs and other cell subsets. We also describe other serum markers of endothelial damage and compare CECs with these markers. Finally, we highlight differences between circulating endothelial cells and endothelial progenitor cells. In summary, CECs must now be regarded as a sensitive and specific marker of endothelial damage. We emphasize that use of CECs in a clinical setting is on the horizon and pathogenetic clues may also be obtained.
Collapse
Affiliation(s)
- Uta Erdbruegger
- Department of Medicine, Division of Nephrology, Hannover Medical School, Carl-Neuberg-Strasse 1, D-30625 Hannover, Germany
| | | | | |
Collapse
|
|
23
|
Miriuka SG, Langman LJ, Evrovski J, Miner SES, Kozuszko S, D'Mello N, Delgado DH, Wong BYL, Ross HJ, Cole DEC. Thromboembolism in Heart Transplantation: Role of Prothrombin G20210A and Factor V Leiden. Transplantation 2005; 80:590-4. [PMID: 16177630 DOI: 10.1097/01.tp.0000170545.42790.6f] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/25/2022]
Abstract
BACKGROUND Thromboembolism has been reported as a frequent complication after cardiac transplantation. Many risk factors for thrombosis may explain this, such as metabolic alterations and the use of cyclosporine. In the general population, two single nucleotide polymorphisms (SNPs), factor V Leiden and prothrombin G20210A (PT G20210A), have been associated with a significant increase in the risk of thrombosis. However, these mutations have not been analyzed in cardiac transplant patients. We describe the protracted history of recurrent thromboembolism in a rare case of homozygosity for the PT G20210A variant. This prompted us to analyze the entire cardiac transplant cohort for the incidence of thromboembolic events and their association with these genetic polymorphisms. METHODS We report the study of 84 cardiac transplant recipients. We retrospectively analyzed the frequency of thromboembolic episodes. The genotypes for FVL and PT G20210A were determined and correlated with those episodes. RESULTS Our results confirm a very high incidence of thromboembolism in this population. We also found a significant increase in the likelihood of thromboembolism in subjects with the PTB G20210A variant (odds ratio 3.08; 95% confidence interval: 1.7-5.5). CONCLUSIONS The incidence of thromboembolic complications after heart transplantation is increased and may be related in part to genetic predisposition.
Collapse
Affiliation(s)
- Santiago G Miriuka
- Department of Medicine, Toronto General Hospital and University of Toronto, Ontario, Canada
| | | | | | | | | | | | | | | | | | | |
Collapse
|
|
24
|
Affiliation(s)
- Santiago Lamas
- Centro de Investigaciones Biologicas and Instituto "Reina Sofia" de Investigaciones Nefrologicas, Consejo Superior de Investigaciones Cientificas, and Centro Nacional de Investigaciones Cardiovasculares, Madrid, Spain.
| |
Collapse
|
|
25
|
Abstract
Cardiac allograft vasculopathy (CAV) is the major obstacle to long-term survival after heart transplantation. It is a rapidly progressive, obliterative form of coronary vasculopathy distinct from classic atheromatous disease. The pathogenesis is most likely multifactorial and involves both alloantigen dependent and independent mechanisms. Since there is no definitive treatment for CAV and new immunosuppressive agents can only slow the progression of this disease, the prophylaxis and modification of numerous risk factors remains the foundation of posttransplant management in the heart transplant recipient. In this review, we discuss current understanding of the pathogenesis of CAV, novel diagnostic and therapeutic avenues and explore optimal approaches to risk factors modification.
Collapse
Affiliation(s)
- Katherine Lietz
- Cardiovascular Division, University of Minnesota, Minneapolis, MN 55455, USA
| | | |
Collapse
|
|
26
|
Silverborn M, Ambring A, Nilsson F, Friberg P, Jeppsson A. Blunted Vascular Response to Endothelin-A Receptor Blockade in Cyclosporine-Treated Lung Transplant Recipients. J Heart Lung Transplant 2005; 24:665-70. [PMID: 15949725 DOI: 10.1016/j.healun.2004.04.010] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2004] [Revised: 03/27/2004] [Accepted: 04/19/2004] [Indexed: 01/14/2023] Open
Abstract
BACKGROUND The majority of cyclosporine-treated transplant recipients develop hypertension. Endothelin-1 (ET-1) has been suggested to mediate cyclosporine-induced vasoconstriction when binding to ET-A receptors. We hypothesized that cyclosporine-treated lung transplant recipients have an increased basal vascular resistance and an augmented response to ET-A receptor blockade. METHODS The selective ET-A receptor blocker BQ-123 (10 and 50 nmol/min) was infused into the brachial artery, alone or in combination with the nitric oxide synthase inhibitor NG-monomethyl-L-arginine acetate (L-NMMA) (2 and 4 micromol/min) in 10 lung transplant recipients without pharmacologically treated hypertension and 8 healthy controls. Forearm blood flow (FBF) was measured by venous occlusion plethysmography and plasma levels of ET-1 were analyzed. RESULTS Baseline forearm vascular resistance did not differ between recipients and controls (32 +/- 4 vs 42 +/- 7 mmHg/ml/min, p = 0.32). BQ-123 increased FBF in controls but not in recipients (26% +/- 9% vs 5% +/- 11% at 10 nmol/min, p = 0.043 between groups). Coinfusion of BQ-123 and L-NMMA caused a comparable decrease in FBF in recipients and controls (-26% +/- 11%, vs -34% +/- 7%). Baseline ET-1 was higher in recipients (17.2 +/- 1.1 vs 14.7 +/- 0.8 pg/ml, p = 0.038). BQ-123 infusion increased plasma ET-1 in controls but not in recipients (+24% +/- 11% vs -0.4% +/- 6.2%, p = 0.029 between groups). CONCLUSIONS The results demonstrate that cyclosporine-treated lung transplant recipients have increased plasma levels of ET-1 and a blunted response to ET-A receptor blockade compared with healthy subjects. In contrast, we found no evidence for an increased basal vascular resistance in transplant recipients. These alterations in endothelin handling may contribute to the development of transplant-associated hypertension.
Collapse
Affiliation(s)
- Martin Silverborn
- Department of Cardiothoracic Surgery, Sahlgrenska University Hospital, Gothenburg, Sweden
| | | | | | | | | |
Collapse
|
|
27
|
El-Hamamsy I, Grant M, Stevens LM, Malo O, Carrier M, Perrault LP. Cyclosporine-induced coronary endothelial dysfunction: is tetrahydrobiopterin the solution? Transplant Proc 2005; 37:2365-70. [PMID: 15964417 DOI: 10.1016/j.transproceed.2005.03.021] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2005] [Indexed: 11/18/2022]
Abstract
BACKGROUND Coronary endothelial dysfunction after heart transplantation is predictive of cardiac allograft vasculopathy. Immunosuppressive drugs, particularly cyclosporine may contribute to this dysfunction by a direct effect. Tetrahydrobiopterin (BH(4)) is a potent antioxidant and an essential cofactor of nitric oxide biosynthesis. The purpose of this study was to investigate whether BH(4) could reverse the endothelial dysfunction induced by cyclosporine. METHODS A previously described in vitro model of drug incubation in Krebs-bicarbonate solution (4 degrees C, 48 hours) of porcine epicardial coronary arteries was used. Coronary endothelial function studies were performed in organ chamber experiments after incubation with cyclosporine (10(-4) mol/L) in the presence or absence of 6-methyltetrahydropterin (MH(4) [0.1 mol/L], a BH(4) analog) to assess its effect on the cyclosporine-induced endothelial dysfunction. RESULTS The average doses of PGF2(alpha) required to attain 50% of the maximal contraction to KCl was significantly lower (P < .001) in the cyclosporine group (8.6 +/- 1.94 x 10(-6) mol/L) compared to the control group (24.8 +/- 5.2 x 10(-6) mol/L). Exposure to cyclosporine induced a significant decrease in endothelium-dependent relaxations to serotonin (5HT) (% E(max) [5HT]: 77% +/- 4%; P < .05). Addition of MH(4) significantly reversed this impaired response (% E(max) [5HT]: 62% +/- 4%; P < .05). No alterations of relaxation were observed with bradykinin in both groups. Endothelium-independent relaxations to sodium nitroprussiate were fully preserved. CONCLUSIONS These results suggest a significant protective role of BH(4) on coronary endothelial function following exposure to cyclosporine, which could reduce the incidence of endothelial dysfunction and cardiac allograft vasculopathy following cardiac transplantation.
Collapse
Affiliation(s)
- I El-Hamamsy
- Research Center, Montreal Heart Institute, 5000 Belanger Street East, Montreal, Quebec H1T 1C8, Canada
| | | | | | | | | | | |
Collapse
|
|
28
|
Ramzy D, Rao V, Tumiati LC, Xu N, Miriuka S, Delgado D, Ross HJ. Tetrahydrobiopterin prevents cyclosporine-induced vasomotor dysfunction. Transplantation 2005; 79:876-81. [PMID: 15849538 DOI: 10.1097/01.tp.0000157364.80712.45] [Citation(s) in RCA: 14] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/27/2022]
Abstract
BACKGROUND Cyclosporine A (CsA) is associated with negative side effects such as endothelial injury, which may lead to transplant vasculopathy. CsA can impair nitric oxide (NO) homeostasis. Therefore, tetrahydrobiopterin (BH4), a NO synthase cofactor, may limit endothelial injury by improving NO production. Our study examines the effect of CsA and BH4 exposure on endothelial function. METHODS Lewis rats were injected with CsA, BH4, CsA+BH4, or saline intraperitoneally daily for 2 weeks. With use of a small vessel myograph, thoracic aortic segments were assessed for endothelial-dependent (Edep) and independent relaxation after exposure to acetylcholine and sodium nitroprusside. Sensitivity to vasospasm was evaluated after exposure to endothelin (ET)-1. RESULTS CsA exposure resulted in impaired Edep vasorelaxation compared with control (P=0.01). BH4 attenuated the deleterious effects of CsA. Compared with control, all treatment groups demonstrated significantly increased sensitivity to ET-1. Furthermore, endothelial nitric oxide synthase expression in the thoracic aorta was reduced after CsA treatment, and this reduction was attenuated by BH4 therapy (P<0.01). ETA receptor expression in the aorta was increased after CsA treatment, but BH4 treatment prevented CsA-induced ETA over-expression (P=0.004). However, ETB receptor expression was increased by BH4 treatment compared with CsA and control (P=0.02). CONCLUSION Our findings suggest that CsA-induced vasomotor dysfunction is a result of alterations in both NO and ET-1 regulation and that BH4 may prevent the deleterious effects of CsA. However, the beneficial effects of BH4 are associated with increased sensitivity to ET-1. Therefore, a combination of BH4 and ET-1 blockade may prove to be an ideal combination for preservation of endothelial function.
Collapse
Affiliation(s)
- Danny Ramzy
- Heart Transplant Program, Toronto General Hospital, University Health Network, Toronto, Ontario M5G 2C4, Canada
| | | | | | | | | | | | | |
Collapse
|
|
29
|
Erdem SR, Tuncer M. Involvement of endothelin and nitric oxide in cyclosporine A-induced contractions in guinea pig isolated gallbladder strips. Pharmacol Res 2005; 51:247-53. [PMID: 15661575 DOI: 10.1016/j.phrs.2004.08.008] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 08/17/2004] [Indexed: 11/16/2022]
Abstract
The involvement of endothelin (ET), ET(A) receptors and nitric oxide (NO) in the contractions induced by cyclosporine A (CyA) were investigated in guinea pig isolated gallbladder strips. Both BQ-123, a selective ET(A) receptor antagonist, and phosphoramidon, an ET converting enzyme inhibitor, inhibited the contractile responses to the parenteral and oral CyA preparations, whereas l-NOARG, a NO synthase inhibitor, potentiated these contractions. Additionally, the pattern of the concentration-dependent contractions in response to ET-1 was similar to that of CyA preparations in gallbladder strips. Both bosentan, a non-selective ET receptor antagonist, and BQ-123 inhibited the ET-1-induced contractions. These findings suggest that an ET-1-mediated mechanism contributes to the contractile response to CyA preparations in guinea pig isolated gallbladder strips. ET(A) receptor activation is likely to be involved in this process. We also speculate that CyA-induced stimulation of NO production might act as a counter-regulatory mechanism in the effect of CyA preparations in this tissue.
Collapse
Affiliation(s)
- S Remzi Erdem
- Department of Pharmacology, Faculty of Medicine, Hacettepe University, Turkey.
| | | |
Collapse
|
|
30
|
Fischereder M, Land W. Etiology of cardiovascular diseases in the transplant population: will the choice of immunosuppressant matter? Transplant Proc 2004; 36:1993-4. [PMID: 15518721 DOI: 10.1016/j.transproceed.2004.08.111] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
Affiliation(s)
- M Fischereder
- Nephrologisches Zentrum, Medizinische Poliklinik, Klinikum Innenstadt der Ludwig-Maximilians-Universität, Munich, Germany.
| | | |
Collapse
|
|
31
|
El-Mas MM, Mohy El-Din MM, El-gowilly SM, Sharabi FM. Regional and endothelial differences in cyclosporine attenuation of adenosine receptor-mediated vasorelaxations. J Cardiovasc Pharmacol 2004; 43:562-73. [PMID: 15085068 DOI: 10.1097/00005344-200404000-00012] [Citation(s) in RCA: 29] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/18/2023]
Abstract
The present study investigated the acute effects of the immunosuppressant drug cyclosporine A on vasorelaxations evoked via activation of adenosine receptors in the phenylephrine-preconstricted rat perfused kidney and isolated aorta. The roles of endothelial relaxing factors in this interaction were also evaluated. The adenosine analogue 5'-N-ethylcarboxamidoadenosine (NECA; kidney, 6 x 10(-9)-1 x 10(-7) mol; aorta, 1 x 10(-9)-1 x 10(-5) M) elicited dose-dependent vasorelaxations. In the perfused kidney, NECA responses were similarly and significantly attenuated by N-nitro-L-arginine methyl ester (L-NAME, nitric oxide synthase inhibitor) or tetraethylammonium (K channel blocker) versus no effect for diclophenac (cyclooxygenase inhibitor). NECA relaxations in the aorta were reduced by the three inhibitors; the reduction in the response evoked by the highest dose of NECA (1 x 10(-5) M) amounted to 37.7 +/- 2.0% (L-NAME), 19.8 +/- 1.7% (tetraethylammonium), and 29.4 +/- 1.1% (diclophenac). A combination of the three inhibitors almost abolished NECA relaxations in the two preparations. Cyclosporine (2 microM) reduced NECA relaxations in the two preparations. In the aorta, cyclosporine attenuation of NECA responses was significantly reduced after exposure to L-NAME or diclophenac but not tetraethyl-ammonium, suggesting selective involvement of nitric oxide and vasodilator prostanoids in the interaction. In contrast, the cyclosporine attenuation of NECA responses in the kidney was reduced by L-NAME or tetraethylammonium. L-arginine, a nitric oxide substrate, partially restored NECA relaxations in cyclosporine-treated preparations. These findings demonstrate that cyclosporine attenuates endothelium-dependent vasorelaxations elicited via activation of adenosine receptors and highlight the interesting possibility that the relative contribution of the endothelial relaxing factors to cyclosporine-NECA interaction is largely region dependent.
Collapse
Affiliation(s)
- Mahmoud M El-Mas
- Department of Pharmacology, Faculty of Pharmacy, University of Alexandria, Alexandria, Egypt.
| | | | | | | |
Collapse
|
|
32
|
Vamvakopoulos JE, Aavik E, Häyry P. Healing the vasculature: angioprotective therapy moves from the bench to the clinic. Transplant Rev (Orlando) 2004. [DOI: 10.1016/j.trre.2004.04.001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/26/2022]
|
|
33
|
Chu Y, Wu YC, Chou YC, Liu HP, Chu JJ, Lin PJ. Cyclosporine enhances vasorelaxation in coronary but not pulmonary artery after 16-hour preservation with UW solution. Transplant Proc 2003; 35:3139-41. [PMID: 14697998 DOI: 10.1016/j.transproceed.2003.10.071] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/26/2022]
Abstract
Cyclosporine (CsA), a calcineurin inhibitor, has been associated with endothelial dysfunction in transplant patients. Human and in vitro studies suggest that CsA produces endothelial dysfunction by impairing vascular endothelium-dependent relaxation. However, little is know about the CsA effects to modulate the vasorelaxation after prolonged graft preservation. In this study using a protocol designed to eliminate the influences of infusion pressure and shear stress, we evaluated the effect of CsA on vasorelaxation of coronary and pulmonary arteries after 16-hour University of Wisconsin (UW) solution preservation.
Collapse
Affiliation(s)
- Y Chu
- Division of Thoracic and Cardiovascular Surgery, Chang Gung Memorial Hospital, Tao Yuan Hsien, Kwei-Shan 333, Taiwan, ROC
| | | | | | | | | | | |
Collapse
|
|
34
|
Rezzani R, Rodella L, Dessy C, Daneau G, Bianchi R, Feron O. Changes in Hsp90 expression determine the effects of cyclosporine A on the NO pathway in rat myocardium. FEBS Lett 2003; 552:125-9. [PMID: 14527673 DOI: 10.1016/s0014-5793(03)00898-6] [Citation(s) in RCA: 30] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/09/2023]
Abstract
Cyclosporine A (CsA) is associated with the development of cardiovascular toxicity in transplant patients but can exert myocardial protection against ischemia/reperfusion damages. We examined in a rat model of chronic CsA administration whether subtle variations in the NO pathway could account for these opposite effects. CsA treatment rapidly led to an increase in myocardial Hsp90 expression promoting the recruitment of Akt and calcineurin, thereby promoting eNOS activation through Ser1177 phosphorylation and Thr495 dephosphorylation, respectively. This was associated with an increase in myocardial VEGF expression and led to anti-apoptotic effects in isolated cardiac myocytes. Upon longer CsA exposure, cardiac toxicity developed, as documented by the infiltration of connective tissue and the increase in iNOS expression. These later effects were associated with a dramatic decrease in the abundance and scaffold function of Hsp90, thereby unraveling the key role of Hsp90 in governing CsA effects.
Collapse
Affiliation(s)
- Rita Rezzani
- Department of Biomedical Sciences and Biotechnology, University of Brescia, Brescia, Italy
| | | | | | | | | | | |
Collapse
|
|
35
|
Woywodt A, Schroeder M, Gwinner W, Mengel M, Jaeger M, Schwarz A, Haller H, Haubitz M. Elevated numbers of circulating endothelial cells in renal transplant recipients. Transplantation 2003; 76:1-4. [PMID: 12865778 DOI: 10.1097/01.tp.0000074569.65127.26] [Citation(s) in RCA: 71] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
Abstract
BACKGROUND Damage of microvascular endothelial cells is a salient feature of acute vascular rejection and chronic allograft nephropathy, yet specific blood markers of ongoing endothelial injury are currently unavailable. Circulating endothelial cells have recently been established as a novel marker of endothelial damage in a variety of vascular disorders. METHODS We studied 129 renal transplant recipients who underwent percutaneous graft biopsy. Circulating endothelial cells were isolated with immunomagnetic anti-CD146-coated Dynabeads. Cells were stained with acridine and counted. To verify their endothelial origin, staining for Ulex europaeus lectin 1 (UEA-1) was performed in parallel. Twenty-one healthy controls were also studied. RESULTS On biopsy, seven patients had acute vascular rejection, 15 patients had acute tubulointerstitial rejection, 14 patients had borderline rejection, and 93 patients had no rejection. Patients with acute vascular rejection had the highest cell numbers (72+/-39 cells/mL) when compared with all other patients (P<0.02). Regardless of their biopsy findings, however, all other renal transplant recipients had significantly higher numbers of circulating endothelial cells (25+/-20 cells/mL) than healthy controls (7+/-5 cells/mL, P<0.001). Finally, there was a significant correlation of cell numbers and serum cyclosporine A trough levels. By contrast, there was no correlation with serum creatinine, age, or the number of immunosuppressive drugs. CONCLUSIONS The number of circulating endothelial cells is a novel marker of endothelial damage in renal transplant recipients. Further studies must now evaluate the origin of these cells, corroborate the clinical significance of our findings, and delineate the influence of calcineurin inhibitors.
Collapse
Affiliation(s)
- Alexander Woywodt
- Department of Medicine, Hannover Medical School, Hannover, Germany. woywodt.alexander@ mh-hannover.de
| | | | | | | | | | | | | | | |
Collapse
|
|
36
|
Perrault LP, Malo O, Bidouard JP, Villeneuve N, Vilaine JP, Vanhoutte PM. Inhibiting the NO pathway with intracoronary L-NAME infusion increases endothelial dysfunction and intimal hyperplasia after heart transplantation. J Heart Lung Transplant 2003; 22:439-51. [PMID: 12681422 DOI: 10.1016/s1053-2498(02)00494-1] [Citation(s) in RCA: 14] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022] Open
Abstract
BACKGROUND The endothelium protects the vascular wall through the nitric oxide (NO) release. Coronary endothelial dysfunction occurs early after heart transplantation and predicts the development of intimal thickening typical of graft coronary vasculopathy. OBJECTIVE We designed this study to examine the effect of endothelial NO synthase (eNOS) inhibition on the endothelial dysfunction caused by rejection and on the development of accelerated atherosclerosis after heart transplantation. METHODS To study the effect on these 2 end-points of inhibiting eNOS with intracoronary L-nitro arginine methyl ester (L-NAME; 1 mg/kg/day), infused with an osmotic pump for 30 days, we used a porcine model of heterotopic heart transplantation with pre-operative immunologic typing, to permit slow rejection without the need for immunosuppression. The endothelium-dependent relaxations of allografted coronary arteries, allografted arteries infused with L-NAME, allografted arteries mounted with the pump, and vehicle and native coronary arteries were compared 30 days after graft implantation using standard organ chamber experiments. We evaluated intimal thickening using a semi-quantitative scale (0-4+ grading). RESULTS A significant decrease in relaxations to serotonin (5-HT) occurred in allografted arteries infused directly with L-NAME compared with allografted arteries from swine receiving 5-HT, and relaxations in the latter were decreased compared with those of swine receiving the vehicle and native coronary arteries (p < 0.05). We found no significant differences in endothelium-dependent relaxations to bradykinin among coronary rings from all groups. We observed a significant increase in the prevalence and severity of intimal thickening in allografted coronary arteries infused with L-NAME compared with allografts not infused (p < 0.05), which had significantly more intimal thickening compared with native coronary arteries (p < 0.05). CONCLUSION These results demonstrate that inhibiting the NO pathway worsens the endothelial dysfunction caused by rejection after heart transplantation and accelerates the intimal thickening process, leading to graft coronary vasculopathy. Strategies designed to preserve endothelial integrity and function of the endothelial NO pathway should be used to prevent graft coronary vasculopathy.
Collapse
Affiliation(s)
- Louis P Perrault
- Department of Surgery, Montreal Heart Institute, Montréal, Québec, Canada
| | | | | | | | | | | |
Collapse
|
|
37
|
Abstract
Cardiovascular disease is one of the major causes of morbidity and mortality following solid organ transplantation. Many of the current immunosuppressive drugs are associated with an increase of one or more risk factors for the development of atherosclerosis. This review compares the mechanism by which individual immunosuppressive agents may impact on these risk factors and the differential contribution of cyclosporine, tacrolimus, mycophenolate, azathioprine, and Rapamycin to these individual risk factors. Attention to the potential cardiovascular toxicities of individual immunosuppressive agents may help design strategies for maintenance of immunosuppression tailored to individual patients.
Collapse
Affiliation(s)
- Leslie W Miller
- Cardiovascular Division, University of Minnesota, Minneapolis, USA.
| |
Collapse
|
|
38
|
Navarro-Antolín J, López-Muñoz MJ, Soria J, Lamas S. Superoxide limits cyclosporine-A-induced formation of peroxynitrite in endothelial cells(2). Free Radic Biol Med 2002; 32:702-11. [PMID: 11937296 DOI: 10.1016/s0891-5849(02)00761-x] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/28/2022]
Abstract
Peroxynitrite (ONOO(-)) is a potent oxidant formed by the nonenzymatic reaction between superoxide anion (O(2)(*-)) and nitric oxide (NO*) in a one-to-one stoichiometry. Accumulated evidence suggests that endothelial dysfunction coincides with an enhanced NO* synthase expression and O(2)(*-) production, facilitating ONOO(-) formation. In vivo, formation of ONOO(-) has been associated with atherosclerosis and vascular aging. The immunosuppressor Cyclosporine A (CsA) has been associated to human endothelial dysfunction and accelerated atherosclerosis. We have previously shown that CsA induced a transcriptionally mediated increase of the eNOS gene expression and that CsA induced the formation of nitric oxide, O(2)(*-), and ONOO(-) in vascular endothelial cells. In this work, we evaluate the CsA-induced relative amounts of formation of O(2)(*-) and NO*, providing data consistent with a role of O(2)(*-), and not NO*, as the limiting factor in the CsA-dependent intracellular formation of ONOO(-) in vascular endothelial cells. Furthermore, when endothelial cells were treated with CsA in a situation of increased generation of superoxide such as that provided by high glucose levels, a further increase in the formation of peroxynitrite was detected. The temporal availability of O(2)(*-) for peroxynitrite formation may thus become critical in the pathophysiological scenarios where reactive nitrogen intermediates are operative.
Collapse
Affiliation(s)
- Javier Navarro-Antolín
- Centro de Investigaciones Biológicas and Instituto Reina Sofía de Investigaciones Nefrológicas, Madrid, Spain
| | | | | | | |
Collapse
|
|
39
|
Harris MB, Ju H, Venema VJ, Liang H, Zou R, Michell BJ, Chen ZP, Kemp BE, Venema RC. Reciprocal phosphorylation and regulation of endothelial nitric-oxide synthase in response to bradykinin stimulation. J Biol Chem 2001; 276:16587-91. [PMID: 11340086 DOI: 10.1074/jbc.m100229200] [Citation(s) in RCA: 288] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/10/2023] Open
Abstract
Endothelial nitric-oxide synthase (eNOS) is phosphorylated at Ser-1179 (bovine sequence) by Akt after growth factor or shear stress stimulation of endothelial cells, resulting in increased eNOS activity. Purified eNOS is also phosphorylated at Thr-497 by purified AMP-activated protein kinase, resulting in decreased eNOS activity. We investigated whether bradykinin (BK) stimulation of bovine aortic endothelial cells (BAECs) regulates eNOS through Akt activation and Ser-1179 or Thr-497 phosphorylation. Akt is transiently activated in BK-stimulated BAECs. Activation is blocked completely by wortmannin and LY294002, inhibitors of phosphatidylinositol 3-kinase, suggesting that Akt activation occurs downstream from phosphatidylinositol 3-kinase. BK stimulates a transient phosphorylation of eNOS at Ser-1179 that is correlated temporally with a transient dephosphorylation of eNOS at Thr-497. Phosphorylation at Ser-1179, but not dephosphorylation at Thr-497, is blocked by wortmannin and LY294002. BK also stimulates a transient nitric oxide (NO) release from BAECs with a time-course similar to Ser-1179 phosphorylation and Thr-497 dephosphorylation. NO release is not altered by wortmannin. BK-stimulated dephosphorylation of Thr-497 and NO release are blocked by the calcineurin inhibitor, cyclosporin A. These data suggest that BK activation of eNOS in BAECs primarily involves deinhibition of the enzyme through calcineurin-mediated dephosphorylation at Thr-497.
Collapse
Affiliation(s)
- M B Harris
- Vascular Biology Center, Department of Pediatrics, Medical College of Georgia, Augusta, Georgia 30912, USA
| | | | | | | | | | | | | | | | | |
Collapse
|
|
40
|
Frapier JM, Choby C, Mangoni ME, Nargeot J, Albat B, Richard S. Cyclosporin A increases basal intracellular calcium and calcium responses to endothelin and vasopressin in human coronary myocytes. FEBS Lett 2001; 493:57-62. [PMID: 11278005 DOI: 10.1016/s0014-5793(01)02269-4] [Citation(s) in RCA: 15] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022]
Abstract
Cyclosporin A (CsA) is a widely used immunosuppressive agent with severe side effects including hypertension. Here, we investigated the effects of CsA on intracellular free calcium ([Ca(2+)](i)) and the mechanisms involved in vasoconstriction in cultured human coronary myocytes. We used the Fura-2 technique for Ca(2+) imaging. Acute application of CsA at therapeutic concentrations (0.1-10 micromol/l) had no effect. Chronic exposure to CsA (1 micromol/l) for 24 h induced a small (20 nmol/l) but highly significant increase of basal [Ca(2+)](i) and enhanced the occurrence of spontaneous Ca(2+) oscillations. Endothelin- and vasopressin-induced rises of [Ca(2+)](i) were also enhanced. The demonstration that CsA increases basal [Ca(2+)](i) in addition to its impact on agonist receptor stimulation is of major importance for new therapeutic approaches.
Collapse
Affiliation(s)
- J M Frapier
- Service de Chirurgie Cardiothoracique, INSERM U-390, Hôpital Arnaud de Villeneuve, Montpellier, France
| | | | | | | | | | | |
Collapse
|
|
41
|
Camargo FD, Huey-Louie DA, Finn AV, Sassani AB, Cozen AE, Moriwaki H, Schneider DB, Agah R, Dichek DA. Germline incorporation of a replication-defective adenoviral vector in mice does not alter immune responses to adenoviral vectors. Mol Ther 2000; 2:496-504. [PMID: 11082323 DOI: 10.1006/mthe.2000.0199] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022] Open
Abstract
The utility of adenoviral vectors is limited by immune responses to adenoviral antigens. We sought to develop immune-competent mice in which the immune response to adenoviral antigens was selectively absent. To do so, we generated mice that were transgenic for a replication-defective vector. Adenoviral antigens might be seen as self-antigens by these mice, and the mice could exhibit immunologic tolerance after postnatal exposure to adenoviral vectors. In addition, characterization of these mice could reveal potential consequences of germline transmission of an adenoviral vector, as might occur in a gene therapy trial. Injection of a "null" (not containing a transgene) E1, E3-deleted vector genome into mouse zygotes yielded five founders that were capable of transmitting the vector genome. Among offspring of these mice, transgenic pups were significantly underrepresented: 108 of 255 pups (42%) were transgenic (P<0.02 versus expected frequency of 50%). Postnatal transgenic mice, however, had no apparent abnormalities. Persistence of an adenoviral vector after intravenous injection was equivalent in livers of transgenic mice and their nontransgenic littermates. Transgenic and nontransgenic mice also had equivalent humoral and cellular immune responses to adenoviral vector injection. Mice that are transgenic for an E1, E3-deleted adenoviral genome can be easily generated; however, they are not tolerant of adenovirus. Moreover, germline transmission of an adenoviral vector genome does not prevent generation of a robust immune response after exposure to adenoviral antigens.
Collapse
Affiliation(s)
- F D Camargo
- Gladstone Institute of Cardiovascular Disease, University of California, San Francisco, California 94141, USA
| | | | | | | | | | | | | | | | | |
Collapse
|
|
42
|
Asberg A, Berg KJ, Hartmann A. Each administration of cyclosporin A enhances skin microvascular reactivity in renal transplant recipients. Microvasc Res 2000; 60:81-90. [PMID: 10964582 DOI: 10.1006/mvre.2000.2247] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
Both impaired and enhanced microvascular function have been described in humans on cyclosporin A (CsA) therapy. In the present study we investigated the acute microvascular effects of a single CsA administration in renal transplant recipients on maintenance CsA therapy. Fourteen renal transplant recipients, median age 48 years (range 24-63 years), transplanted 4-12 weeks earlier, were included in this placebo-controlled, double-blinded, crossover study. All recipients had stable renal function; median serum creatinine was 116 micromol/L (range 80-184 micromol/L). Immunosuppressive therapy consisted of CsA, prednisolone, and either azathioprine or mycophenolate. Microvascular function was assessed by laser Doppler flowmetry in combination with acetylcholine (endothelium dependent) stimulation and the postocclusive reactive hyperemia test. Measurements were performed before (control) and 2.5 h following administration of CsA (Neoral) or matching placebo and repeated with reversed medication after at least 6 days. Vasodilative responses to acetylcholine stimulation were significantly higher following CsA ingestion compared with placebo. The mean change in AUC(1.5) (area under the flux versus time curve) from control to 2.5 h was 100 +/-145 for CsA and -292 +/- 140 AU x min for placebo (P = 0.047, n = 10). The postocclusive hyperemic response AUC(rh) was also significantly higher following CsA intake (39 +/- 4 AU x min) compared to placebo (30 +/- 4 AU x min) (P = 0.006, n = 12). This study shows that each dose of CsA induces a transient increase in skin microvascular reactivity in renal transplant recipients. We speculate that this might be due to the potentiation of one or several endothelial-dependent compensatory vasodilative mechanisms in the microvascular bed.
Collapse
Affiliation(s)
- A Asberg
- Laboratory for Renal Physiology, The National Hospital, Oslo, N-0027, Norway
| | | | | |
Collapse
|
|
43
|
Pere AK, Krogerus L, Mervaala EM, Karppanen H, Ahonen J, Lindgren L. Beneficial effects of dietary magnesium and potassium on cardiac and renal morphologic features in cyclosporin A-induced damage in spontaneously hypertensive rats. Surgery 2000; 128:67-75. [PMID: 10876188 DOI: 10.1067/msy.2000.106530] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
BACKGROUND Cyclosporin A-induced hypertension is dependent on the level of dietary salt. We investigated whether dietary magnesium or potassium could protect against cyclosporin A-induced cardiac and renal damage in spontaneously hypertensive rats (SHRs) on high-sodium diet. METHODS Eight-week-old SHRs were divided into 4 groups: (1) receiving a high-sodium diet, (2) receiving a high-sodium, high-potassium diet, (3) receiving a high-sodium, high-magnesium diet, and (4) receiving a high-sodium, high-potassium, high-magnesium diet. The effects of cyclosporin A in SHRs on a relatively low-sodium diet and in normotensive Wistar-Kyoto rats were also examined. Cardiac and renal morphologic condition was assessed, and tissue damage was scored by light microscopy after 6 weeks of cyclosporin A treatment. RESULTS In SHRs on a high-sodium diet, cyclosporin A caused luminal narrowing of the coronary arteries, left ventricular scarring, and damage in the renal arterioli and glomeruli. Dietary magnesium supplementation alone and in combination with potassium protected against these changes, whereas potassium alone was less effective. Cyclosporin A treatment caused only minor histopathologic changes in SHRs receiving a low-sodium diet. Interestingly, the detrimental interaction between cyclosporin A and a high-sodium diet was also observed in normotensive Wistar-Kyoto rats. CONCLUSIONS Dietary magnesium, especially in combination with potassium, protects against cyclosporin A-induced cardiac and renal damage.
Collapse
Affiliation(s)
- A K Pere
- Division of Transplantation Surgery, Fourth Department of Surgery, Helsinki University Central Hospital, Finland
| | | | | | | | | | | |
Collapse
|
|
44
|
Takeda Y, Inaba S, Furukawa K, Fujimura A, Miyamori I, Mabuchi H. Effects of chronic neutral endopeptidase inhibition in rats with cyclosporine-induced hypertension. J Hypertens 2000; 18:927-33. [PMID: 10930191 DOI: 10.1097/00004872-200018070-00015] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/27/2022]
Abstract
OBJECTIVE Cyclosporine (CysA), a potent immunosuppressant, is associated with hypertension and nephrotoxicity. Neutral endopeptidase (NEP) degrades vasoactive peptides, including the natriuretic peptides and endothelin-1 (ET-1). We conducted the present study to determine whether or not the NEP inhibitor, ecadotril, prevents cyclosporine-induced hypertension and to clarify the mechanisms responsible for the hypotensive effects of ecadotril. DESIGN AND METHODS We studied the chronic effects of ecadotril (30 mg/kg per day) on blood pressure; the production of ET-1 and C-type natriuretic peptide (CNP); endothelial nitric oxide synthase (eNOS) activity; and the expression of messenger RNA (mRNA), for each substance in blood vessels of CysA-induced hypertensive rats. RESULTS CysA (25 mg/kg per day) given for 4 weeks increased the blood pressure from 116 +/- 14 mmHg to 159 +/- 15 mmHg, in rats. This increase was blunted by the co-administration of ecadotril (blood pressure: 134 +/- 14 mmHg). CysA increased plasma NEP activity. CysA increased the production of ET-1 and the expression of ET-1 mRNA without affecting CNP synthesis and endothelin converting enzyme (ECE)-1 mRNA expression. CysA decreased the eNOS activity and eNOS mRNA levels. Addition of the NEP inhibitor decreased the synthesis of ET-1 and ET-1 mRNA levels and increased the eNOS activity and the eNOS mRNA levels. Vascular CNP synthesis and ECE-1 mRNA expression in rats treated with ecadotril did not differ from those in rats treated with CysA and ecadotril. CONCLUSION These results indicate that chronic NEP inhibition may prevent the CysA-induced hypertension by decreasing local ET-1 synthesis and partly increasing vascular nitric oxide production.
Collapse
Affiliation(s)
- Y Takeda
- Second Department of Internal Medicine, School of Medicine, Kanazawa University, Japan
| | | | | | | | | | | |
Collapse
|
|
45
|
Aptecar E, Teiger E, Dupouy P, Benvenuti C, Kern MJ, Woscoboinik J, Sediame S, Pernes JM, Castaigne A, Loisance D, Dubois-Randé JL. Effects of bradykinin on coronary blood flow and vasomotion in transplant patients. J Am Coll Cardiol 2000; 35:1607-15. [PMID: 10807467 DOI: 10.1016/s0735-1097(00)00583-0] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 10/18/2022]
Abstract
OBJECTIVES To evaluate the effects of exogenous bradykinin on coronary epicardial and microcirculatory tone in transplant patients (HTXs), and to compare them with the effects of acetylcholine. BACKGROUND Coronary endothelial dysfunction has been reported to occur early after heart transplantation, most notably when acetylcholine was the endothelium-function marker used. The effects of bradykinin on coronary vasomotion are unknown in HTXs. METHODS Sixteen HTXs were compared 3.6 +/- 1.7 months after transplantation to seven control subjects. Coronary flow velocity was measured using guide-wire Doppler. Diameters (D) of three segments of the left coronary artery and coronary blood flow (CBF) were assessed at baseline, after 3-min infusions of increasing bradykinin doses (50, 150 and 250 ng/min) then of increasing acetylcholine doses (estimated blood concentrations of 10(-8), 10(-7) and 10(-6) M). RESULTS Bradykinin induced similar dose-dependent increases in D and CBF in both groups: D was 11 +/- 12%, 19 +/- 14% and 22 +/- 16% (all p < 0.0001), and CBF was 50 +/- 40%, 130 +/- 68% and 186 +/- 77% (all p < 0.0001). Acetylcholine induced significant epicardial vasodilation in control subjects and vasoconstriction in HTX, as well as a marked increase in CBF in both groups. Acute allograft rejection, present in 8 of the 16 HTXs, did not modify responses to bradykinin, but was associated with a smaller CBF increase in response to acetylcholine (p < 0.05). CONCLUSIONS The coronary vasodilating effects of bradykinin are preserved early after heart transplantation, even in the presence of acute allograft rejection. Although there is an abnormal vasoconstricting response to acetylcholine reflecting endothelium dysfunction, the endothelium remains a functionally active organ in heart transplant recipients.
Collapse
Affiliation(s)
- E Aptecar
- Fédération de Cardiologie et Institut National de la Santé et de la Recherche Médicale U400, Créteil, France.
| | | | | | | | | | | | | | | | | | | | | |
Collapse
|
|
46
|
Lee PC, Wang ZL, Qian S, Watkins SC, Lizonova A, Kovesdi I, Tzeng E, Simmons RL, Billiar TR, Shears LL. Endothelial nitric oxide synthase protects aortic allografts from the development of transplant arteriosclerosis. Transplantation 2000; 69:1186-92. [PMID: 10762225 DOI: 10.1097/00007890-200003270-00025] [Citation(s) in RCA: 42] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/26/2022]
Abstract
BACKGROUND Inducible nitric oxide synthase (iNOS) is up-regulated in rejecting allografts and is protective against allograft arteriosclerosis; it suppresses neointimal smooth muscle cell accumulation and inhibits adhesion of platelets and leukocytes to the endothelium. However, the functional importance of endothelial NOS (eNOS) in the rejecting allografts remains unclear. METHODS We examined the effects of selective eNOS deficiency in aortic allografts in a murine chronic rejection model using grafts from eNOS knockout (KO) mice (C57BL/6 background; H2b) and normal C3H (H2K) as recipients. Grafts from wild-type C57BL/6 mice served as controls. Grafts from iNOS KO mice served as a second group of controls where the contribution from iNOS was eliminated but eNOS was preserved. Aortic grafts were harvested and analyzed at days 10-14, 18-22, and 26-30 after transplantation. RESULTS Endothelial NOS-deficient grafts showed significantly increased intima/media ratios at days 26-30 compared to controls. Immunostaining demonstrated that in eNOS KO grafts, eNOS was not detectable whereas iNOS was expressed prominently in infiltrating recipient mononuclear cells. In control grafts, eNOS expression was preserved in the endothelium even by day 30, and associated with a decrease in intimal thickening. We further demonstrated that early overexpression of iNOS by ex vivo gene transfer completely prevented the development of arteriosclerosis associated with eNOS deficiency. CONCLUSIONS We found that eNOS plays a protective role in allografts, and that in eNOS-deficient allografts, early overexpression of iNOS is capable of preventing the development of allograft arteriosclerosis. In allografts with dysfunctional vascular endothelium and impaired eNOS activity as a result of ischemia or native arteriosclerotic disease, iNOS gene therapy may serve to improve their long-term survival and function.
Collapse
Affiliation(s)
- P C Lee
- Department of Surgery, University of Pittsburgh, Pennsylvania 15261, USA
| | | | | | | | | | | | | | | | | | | |
Collapse
|
|
47
|
Morris ST, McMurray JJ, Rodger RS, Farmer R, Jardine AG. Endothelial dysfunction in renal transplant recipients maintained on cyclosporine. Kidney Int 2000; 57:1100-6. [PMID: 10720962 DOI: 10.1046/j.1523-1755.2000.00937.x] [Citation(s) in RCA: 117] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022]
Abstract
BACKGROUND Hypertension is almost universal following renal transplantation and may contribute to the already poor cardiovascular prognosis of this group. Cyclosporine-induced hypertension is a particular problem and has variously been attributed to increased sympathetic nerve activity, salt and water retention, and increased circulating endothelin levels. However, the effects of cyclosporine on the L-arginine/nitric oxide (NO) system in vivo in humans are unknown. In this present study, we examined basal and stimulated NO production from the vascular endothelium in cyclosporine-treated renal transplant recipients using the technique of forearm venous plethysmography. METHODS In study 1, stimulated NO production was assessed in 9 cyclosporine-treated renal transplant recipients (CsA), 7 azathioprine-treated renal transplant recipients (AZA), and 12 controls, using carbachol (an endothelium-dependent vasodilator) and sodium nitroprusside (an endothelium-independent vasodilator). In study 2, basal NO production was assessed in 9 cyclosporine-treated patients and 11 controls using L-NMMA (inhibits NO synthase), with norepinephrine as a control vasoconstrictor. Drugs were infused into the nondominant forearm through a sterile 27-gauge needle, and changes in forearm blood flow (FBF) were measured using venous occlusion plethysmography. RESULTS In study 1, sodium nitroprusside caused a similar dose-dependent increase in FBF in all groups. However, the median (range) percentage increase FBF to carbachol (3 micrograms/min) was markedly reduced in the CsA patients (188.8; 72.5 to 385.1) compared with AZA patients (378.1; 124.0 to 548.9; P = 0.042) and to controls (303.8; 124.8 to 813.3; P = 0.028). In study 2, the maximum percentage reduction in FBF to L-NMMA (4 mumol/min) was less pronounced in CsA patients (-19.5; -4.7 to -63.1) compared with controls (-39.5; -15.7 to -52.8; P = 0.056), and while controls vasoconstricted to the maximum dose of norepinephrine (240 pmol/min) as expected (-26.9; -1.4 to -38.6), CsA patients as a group tended to vasodilate (7.9; -36.8 to 92.6; P = 0.02). CONCLUSION These data demonstrate impaired stimulated and basal NO production in CsA patients, indicating endothelial dysfunction. This may predispose patients to atherosclerosis and may be involved in the etiology of post-transplant hypertension.
Collapse
Affiliation(s)
- S T Morris
- Department of Medicine & Therapeutics, Western Infirmary, Glasgow, Scotland, United Kingdom
| | | | | | | | | |
Collapse
|
|
48
|
Zhang X, Hachida M, Lu H, Hoshi H, Koyanagi H. Effect of 15-deoxyspergualine on coronary arteriosclerosis and platelet-derived growth factor-A mRNA expression in the transplanted heart. Transplant Proc 1999; 31:1706-9. [PMID: 10331045 DOI: 10.1016/s0041-1345(99)00071-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/28/2022]
Affiliation(s)
- X Zhang
- Department of Cardiovascular Surgery, Tokyo Women's Medical College, Japan
| | | | | | | | | |
Collapse
|
|
49
|
Braun-Dullaeus RC, Feussner M, Walker G, Hopmann H, Kraemer HJ, Grimminger F, Tillmanns H, Haberbosch W. Cyclosporine-induced coronary artery constriction--dissociation between thromboxane release and coronary vasospasm. J Heart Lung Transplant 1999; 18:328-35. [PMID: 10226897 DOI: 10.1016/s1053-2498(98)00041-2] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022] Open
Abstract
Cyclosporine influences vascular tone, including that of coronary arteries. But its effect on myocardial prostanoid release, which may contribute to a drug-induced coronary and/or myocardial dysfunction, remains unknown. We used the isolated perfused rat heart to study the effect of cyclosporine on both the mechanical function parameters and myocardial prostanoid release into the effluent by ELISA. Cyclosporine (5 microM) induced an increase of perfusion pressure from 40 +/- 3 to 73 +/- 4 mm Hg within 60 minutes (p < 0.001), reflecting an increase of coronary tone. Cyclosporine did not affect heart rate but contractility (+dp/dtmax) tended to decrease, although not significantly. The drug's effect on coronary tone was rapidly reversible upon withdrawal. Cyclosporine perfusion resulted in an increase of thromboxane B2 liberation from 236 +/- 150 to 1321 +/- 354 pg/ml effluent (p < 0.001), whereas the 6-keto-prostaglandin F1 alpha release was unaffected. The vehicle cremophor did not change any of these parameters. Neither inhibition of myocardial prostanoid formation with acetylsalicylic acid nor thromboxane receptor blockade prevented the cyclosporine-induced increase of perfusion pressure. However, perfusion with nitroglycerin or the voltage-sensitive calcium channel antagonist nifedipine in addition to cyclosporine were able to prevent the increase of perfusion pressure. This is the first time it has been demonstrated that cyclosporine induces an acute release of the prostanoid thromboxane within the myocardium. Despite the resulting imbalance in favor of the vasoconstrictive prostanoid, a dependency of the cyclosporine-induced increase of coronary tone on this imbalance was excluded. Conversely, nitric oxide donation or calcium channel blockade were able to prevent the negative effect of the drug on coronary tone, supporting the concept of endothelium-dependent and/or myogenic mechanism of cyclosporine toxicity on the coronary vascular bed.
Collapse
|
|
50
|
Hachida M, Zhang X, Lu H, Hoshi H, Koyanagi H. Multiglycosidorum tripterygii, a new immunosuppressant, supresses coronary arteriosclerosis after heart transplantation. J Heart Lung Transplant 1999; 18:248-54. [PMID: 10328151 DOI: 10.1016/s1053-2498(98)00015-1] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022] Open
Abstract
BACKGROUND Graft coronary arteriosclerosis is the major limiting factor for long-term survival after heart transplantation. In this study, we investigate the effect of multiglycosidorum tripterygii on graft coronary arteriosclerosis and platelet-derived growth factor A mRNA expression of transplanted hearts. METHODS Three groups of Lewis rats (n = 7/Group) underwent heterotopic heart transplantation from Wistar-King donors and were treated with cyclosporine A (10 mg/ kg/day) for 60 days (Group A) or with multiglycosidorum tripterygii (30 mg/kg/day) for 60 days (Group B) or with cyclosporine A for the first 30 days and followed by multiglycosidorum tripterygii for another 30 days (Group C). Histological evaluations of rejection and coronary arteriosclerosis, as well as Northern blot analysis on graft platelet-derived growth factor A mRNA expression were made 60 days after transplantation. RESULTS Morphometric results indicated no significant difference in rejection among three groups. However, the extent of graft coronary arteriosclerosis in Group B (1.12 +/- 0.21) and Group C (1.41 +/- 0.19) was significantly less than that seen in Group A (1.72 +/- 0.18) (p < 0.01 andp < 0.05, respectively). Furthermore, the incidence of diseased vessels was significantly less in Group B (29.5% +/- 7.8%) and Group C (42% +/- 9.1%) compared with Group A (69.1% +/- 11%) (p < 0.01 and p < 0.05, respectively). The expression of platelet-derived growth factor A mRNA of cardiac allograft was also significantly suppressed in Group B (25.4 +/- 6.2) and Group C (39.8 +/- 9.4), when compared with Group A (62.2 +/- 12.9) (p < 0.01 and p < 0.05, respectively). CONCLUSION Multiglycosidorum tripterygii is superior to cyclosporine in prevention and attenuation of graft coronary arteriosclerosis and this efficacy is probably associated with the depressed expression of graft platelet-derived growth factor A mRNA in the multiglycosidorum tripterygii-treated groups.
Collapse
Affiliation(s)
- M Hachida
- Department of Cardiovascular Surgery, The Heart Institute of Japan, Tokyo Women's Medical College
| | | | | | | | | |
Collapse
|