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J Thorac Cardiovasc Surg 2008;135:938-944
© 2008 The American Association for Thoracic Surgery

Cardiothoracic Transplantation

Dual immunosuppression enhances vasomotor injury: Interactive effect between endothelin-1 and nitric oxide bioavailability

Danny Ramzy, MD, Laura C. Tumiati, BSc, Elissa Tepperman, BSc, Rohit Sheshgiri, BSc, Jessica Jackman, BSc, Mitesh Badiwala, MD, Vivek Rao, MD, PhD*

Heart Transplant Program, Peter Munk Cardiac Center, Toronto General Hospital; Division of Cardiac Surgery, University of Toronto; and Division of Cardiology, University of Toronto, Toronto, Ontario, Canada

Received for publication May 14, 2007; revisions received August 18, 2007; accepted for publication September 6, 2007.

* Address for reprints: Vivek Rao, MD, PhD, Toronto General Hospital, Division of Cardiovascular Surgery, 4N-464, 200 Elizabeth Street, Toronto, Ontario, Canada M5G 2C4. (Email: vivek.rao{at}uhn.on.ca).


   Abstract
Top
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 Conclusions
 References
 
Objective: Cyclosporine A and corticosteroids are associated with many side effects, such as endothelial dysfunction and transplant vasculopathy. We examined the effects of cyclosporine A and hydrocortisone exposure on endothelial function of the rat thoracic aorta.

Methods: Lewis rats were injected with cyclosporine A, hydrocortisone, cyclosporine A + hydrocortisone, or intraperitoneal saline daily for 2 weeks. Endothelial-dependent and independent vascular relaxation were assessed in isolated segments of thoracic aorta, as well as endothelin-1–induced vasoreactivity. Protein expression of endothelial nitric oxide synthase, endothelinA, and endothelinB receptors were also determined in the thoracic aorta.

Results: Exposure to cyclosporine A and cyclosporine A + hydrocortisone resulted in a reduction in endothelial-dependent vasorelaxation compared with control and hydrocortisone (P = .001). Cyclosporine A and hydrocortisone-treated rats demonstrated increased vasoreactivity to endothelin-1 compared with control, whereas cyclosporine A + hydrocortisone treatment resulted in a synergistic increase (P = .04). All treatment groups displayed a significant reduction in endothelial nitric oxide synthase expression compared with control (P = .001). EndothelinA receptor expression was increased in all treatment groups with a synergistic effect seen after cyclosporine A + hydrocortisone treatment. No differences were seen in endothelinB receptor expression.

Conclusion: Cyclosporine A and hydrocortisone induce vasomotor dysfunction with a synergistic impairment observed after concomitant exposure. Our findings suggest that the resultant vasomotor dysfunction is the result of alterations in both nitric oxide and endothelin-1 regulation.

Abbreviations and Acronyms CyA = cyclosporine A; eNOS = endothelial nitric oxide synthase; ET = endothelin; Hcort = hydrocortisone; LV = left ventricular; NO = nitric oxide; Rc = receptor; SNP = sodium nitroprusside; TAo = thoracic aorta


   Introduction
Top
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 Conclusions
 References
 
Cyclosporine A (CyA) was the first antirejection drug that affected the results of clinical heart transplantation by reducing the incidence and severity of rejection and remains an important component of modern immunosuppressive therapy. Unfortunately, CyA is associated with many negative side effects, such as nephrotoxicity, hepatotoxicity, neurotoxicity, and hypertension.1-3Go Other adverse effects include endothelial dysfunction and the development of transplant vasculopathy.1,4-10Go CyA can influence transplant vasculopathy by increased plasma lipid concentrations, causing hypertension, or by direct injury to the endothelium.10-13Go It is believed that the endothelial injury induced by CyA results in impaired vascular homeostasis and transplant coronary disease.

The mechanisms by which CyA results in endothelial dysfunction are not fully elucidated. However, CyA is known to impair vasodilation14-17Go and may induce vasoconstriction.18-20Go Potential mechanisms resulting in vasospasm include the increased release of vasoconstrictors or increased sensitivity to these vasoconstrictors. One such vasoconstrictor is endothelin (ET)-1. The effect of CyA on plasma levels of ET-1 remains controversial. Most investigators have found an increase in ET-1 levels after CyA treatment, although this is not a consistent finding.15,19,21-27Go Furthermore, altered nitric oxide (NO) homeostasis may result in an impaired vasodilatory response.15Go Impaired NO homeostasis may be a result of decreases in mRNA or protein expression of endothelial nitric oxide synthase (eNOS) in CyA-treated patients. Several investigators have demonstrated that eNOS RNA expression is increased after CyA treatment,28Go suggesting that impaired NO production may be due to decreases in eNOS protein synthesis or a shift to free radical production.29Go There is also evidence that CyA generates free radicals.4Go These free radicals may result in direct endothelial injury and impaired vasomotor function.

Corticosteroids are another commonly used antirejection agent also associated with several side effects. Corticosteroids can inhibit the release of vasodilators, such as histamine and prostacyclin. We hypothesized that the combination of CyA and corticosteroids (commonly used after solid organ transplantation) results in a synergistic impairment of vascular function. Our investigations assessed the role of CyA, and hydrocortisone (Hcort) on the development of endothelial dysfunction in a rodent model of vascular injury. Although these investigations have direct relevance to transplant vasculopathy, we intentionally avoided a transplant model to eliminate the confounding effects of immune-mediated injury. Thus, these studies evaluate the drug-specific changes to vascular function after sustained exposure. Specifically, we examined the effects of CyA and Hcort exposure on NO homeostasis and ET-1 signaling.


   Materials and Methods
Top
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 Conclusions
 References
 
Animal care conformed to the "Canadian Council on Animal Care Guide to the Care and Use of Experimental Animals" (National Institutes of Health publication no 86-23, revised 1996).

Male Lewis rats (n = 16) (200–300 g) were administered the drug of interest (saline control, CyA (5 mg/kg) or Hcort (20 mg/kg)) via peritoneal injection daily for a period of 2 weeks before assessment of endothelial function. On the day of sacrifice, rats were anesthetized using isoflurane. Median sternotomy was then performed, the heart was excised for myocardial tissue sampling, and segments of aorta were procured for assessment of endothelial function. Before heart excision, 1 mL of blood from the right ventricle was collected for analysis of ET-1 plasma levels. The rats were then exsanguinated under general anesthesia.

Endothelial Function Assessment
Endothelial-dependent and independent vascular relaxation were assessed in isolated segments of thoracic aorta (TAo) after treatment. The TAo was dissected, and vascular segments (5 mm in length) were used for the assessment of in vitro vascular function using a small vessel myograft for isometric tension recording. After mounting the vessel on a pressure transducer, maximum vasoconstriction was achieved with exposure to phenylephrine. After stabilization, endothelial-dependent relaxation was assessed by incremental exposure to acetylcholine. Endothelial-independent relaxation was assessed by incremental exposure to sodium nitroprusside (SNP). The maximum relaxation from phenylephrine-induced vasoconstriction (Emax%) was compared between groups. ED50, calculated as the concentration required to achieve half-maximum vasorelaxation, was compared between groups. Sensitivity to vasospasm was assessed in vessels following stabilization after SNP washout. Incremental exposure to ET-1 was performed, and %Cmax was calculated as the maximum increase in tension from baseline. Each animal yielded 2 aortic segments. Data were included if the variability between segments was less than 10%, and data were averaged to yield 1 result per animal.

Plasma Measurements
Venous blood was aspirated from the right ventricle before exsanguination. CyA trough levels were performed on whole blood. For ET-1 levels, blood samples were centrifuged (14,000 rpm) to collect the plasma fraction, which was snap-frozen in liquid nitrogen and stored at –80°C. ET-1 in plasma was extracted using C18 Sep-Pack (Waters Corporation, Milford, Mass) columns after acidification with 1% trifluoroacetic acid. Plasma ET-1 levels were measured using a commercial enzyme-linked immunosorbent assay (Biomedica, Vienna, Austria).

Assessment of Oxidative Injury
8-isoprostane levels were measured as an indicator of free radical-mediated injury.30Go 8-isoprostane is the stable end product of arachidonic acid oxidation generated by reactive oxygen species injury.31Go Determination of 8-isoprostane levels in left ventricular (LV) myocardial tissue was performed using a commercially available kit (Cayman Chemical Company, Ann Arbor, Mich). The percentage from baseline (LV from animals that received no intraperitoneal injections) was calculated to compare differences between groups.

Western Blot Analysis
LV biopsies and the TAo were immediately collected after harvesting. Biopsy specimens were snap-frozen in liquid nitrogen and stored at –80°C until analyzed. Biopsies were homogenized at 4°C and prepared for analysis. Protein determination was determined by the method described by Bradford.32Go

Western blot determined the protein expression of inducible NOS, eNOS, tumor necrosis factor-{alpha}, and transforming growth factor-β with the use of protein-specific monoclonal antibodies (BD Biosciences, Mississauga, Canada) and ETA and ETB receptors (Rc's) with the use of protein-specific polyclonal antibodies (Chemicon, Temecula, Calif). Samples were separated using 4% stacking and 10% running tris-glycine sodium dodecylsulfate–polyacrylamide gel electrophoresis gels. Gels were then transferred to polyvinylidene difluoride membranes. Blocking was performed for 1 hour at room temperature using blocking buffer. The blots were exposed to the primary antibody for 12 hours at 4°C and then incubated with secondary antibody for 1 hour after washing. Comparisons between groups were performed using densitometric analysis. TAo densitometric data were corrected for β-actin expression, and LV data were corrected for glyceraldehyde-3-phosphate dehydrogenase expression. No differences in β-actin and glyceraldehyde-3-phosphate dehydrogenase protein expression were seen between groups at any time point.

Statistical Analysis
Statistical analysis was performed with the SAS statistical software program V8.2 (SAS institute, Inc, Cary, NC). Continuous data were analyzed by analysis of variance and are expressed as the mean ± standard deviation. When the F-statistic of the analysis of variance was significant (P < .05), a Duncan's multiple range test was performed to specify differences between groups.


   Results
Top
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 Conclusions
 References
 
All animals survived until the day of sacrifice with no complications except for 1 rat with a gingival abscess in the Hcort group. There was minimal variability from aortic segments within each animal, and no animals were excluded from the study. CyA levels in both treatment groups were similar: CyA (61.7 ± 11 ng/mL) and CyA + Hcort (63.2 ± 9 ng/mL).

Endothelial Function
Endothelial-dependent vasorelaxation of thoracic aortic rings was impaired after CyA treatment compared with control (Go Figure 1, A). CyA and CyA + Hcort treatment resulted in an Emax% of 33% ± 2% and 30% ± 7%, respectively, which was significantly (P = .001) lower than that of control at 46% ± 1%. However, isolated Hcort treatment (Emax%: 51% ± 1%) did not result in any significant impairment of endothelial-dependent vasorelaxation compared with control. Assessment of endothelial-independent Emax% to SNP revealed no significant differences between groups (P = .2) (Figure 1, B). However, when examining the concentration of SNP necessary to achieve 50% of maximal vasodilatory response, significant differences were seen between groups. CyA-treated (ED50 3.2 x 10–8 ± 0.2 mole/L) and CyA + Hcort-treated (ED50 4.0 x 10–8 ± 0.3 mole/L) animals required approximately double the concentration of SNP compared with both control (ED50 1.6 x 10–8 ± 0.1 mole/L) and Hcort (ED50 1.3 x 10–8 ± 0.1 mole/L) (P = .01). Differences between CyA + Hcort and CyA alone were also significant (P < .05).


Figure 1
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  		Figure 1. A, Endothelial-dependent vasodilation in rat TAo. The graph depicts the cumulative dose-response curves to acetylcholine in aortic segments. CyA and CyA + Hcort treatment results in impaired endothelial-dependent vasorelaxation compared with Hcort and control. B, Endothelial-independent vasodilation in rat TAo. The graph depicts the cumulative dose-response curves to SNP in aortic segments. No differences in %Emax were seen between groups. C, Cumulative dose-response curves to ET-1 in aortic segments of treated rats. Both CyA and Hcort increase vasosensitivity to ET-1. Concomitant treatment synergistically increases vessel sensitivity to ET-1. CyA, Cyclosporine A; Hcort, hydrocortisone; ET, endothelin; Con, control; Ach, acetylcholine.

 
Significant differences were also found in vessel sensitivity to ET-1 exposure. Sensitivity to vasospasm (%Cmax) was greater in CyA and Hcort-treated groups (P = .04) compared with control (CyA: 256% ± 11% vs Hcort: 238% ± 7% vs control: 209% ± 7%) (Figure 1, C). Concomitant treatment with CyA + Hcort (%Cmax: 348% ± 10%) resulted in a synergistic increase in ET-1 induced vasospasm compared with CyA and Hcort treatment alone.

Plasma Endothelin-1 Levels
Plasma ET-1 levels were not different between groups (CyA + Hcort: 1.0. ± 0.1 fmol/L vs CyA: 0.98 ± 0.1 fmol/L vs Hcort: 0.97 ± 0.1f mol/L vs control: 0.97 ± 0.1 fmol/L, P = .05). Control animals had an ET-1 plasma concentration that is in the expected normal range.19Go

Oxidative Injury
CyA + Hcort and CyA treatment resulted in a greater increase in oxidative injury as measured by changes in 8-isoprostane levels compared with both control and Hcort groups (CyA + Hcort: 162% ± 9% vs CyA: 150% ± 6% vs Hcort: 113% ± 2% vs control: 107% ± 4%, P = .05).

Endothelin Receptor Expression
Thoracic aortic ETA Rc protein expression was significantly (P = .004) increased in all treatment groups compared with control with concomitant treatment, resulting in an additive increase in ETA Rc expression (Go Figure 2, A and B). However, ETB Rc protein expression was not different between groups (P = .29).


Figure 2
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  		Figure 2. A, Quantitative Western blot analysis of ETA Rc expression in the TAo. All treatment groups showed increased ETA Rc expression, with the greatest increase observed in the CyA + Hcort group. B, Quantitative Western blot analysis of ETB Rc protein expression in the TAo. No differences were observed between groups. C, Quantitative Western blot analysis of eNOS protein expression in the TAo. Both CyA and Hcort decreased eNOS expression, with CyA + Hcort demonstrating a synergistic reduction. ET, Endothelin; Rc, receptor; Con, control; CyA, cyclosporine A; Hcort, hydrocortisone; eNOS, endothelial nitric oxide synthase.

 
Nitric Oxide Synthase Expression
eNOS protein expression was lower in treated animals (CyA and Hcort) compared with control (P < .001) (Figure 2, C). However, CyA + Hcort exposure resulted in a significant synergistic reduction in eNOS protein expression. However, inducible NOS expression was not induced in any of the experimental groups.

Proinflammatory Cytokine Expression
Myocardial protein expression of tumor necrosis factor-{alpha} and transforming growth factor-β did not differ between groups.


   Discussion
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
Conclusions
 References
 
CyA is the cornerstone of modern immunosuppressive therapy despite its well-known side effects. Jeanmart and colleagues33Go demonstrated that CyA results in impairment of endothelial-dependent vasorelaxation in an in vitro model. Sudhir and colleagues17Go and Khalil and colleagues34Go have both shown in dogs that acute exposure to CyA impairs coronary endothelial function. Their results also indicate that NO dysregulation may be involved in CyA-induced dysfunction.17,34Go Our study confirms that both CyA and Hcort result in vasomotor dysfunction in an in vivo model. The mechanisms of injury are different between the 2 agents, and when they were administered concomitantly, we observed a synergistic impairment of vascular function. The possible mechanisms of vascular injury include direct oxidant injury, increased cytokine release, and altered regulation of endothelial NO production.

We demonstrated that CyA treatment significantly alters normal vascular homeostasis as assessed by impaired endothelial-dependent vascular dilatation. Normal vessel function is maintained by the balance between NO and ET-1. Our study revealed that CyA alters both NO and ET-1 regulation. First, eNOS protein expression was reduced after treatment with CyA, indicating a possible impairment in NO regulation. The reduction in eNOS protein expression may be a consequence of CyA inhibiting cyclophilin cis-trans peptidyl-prolyl isomerase function, resulting in impaired eNOS folding and therefore increased degradation. Lungu and colleagues35Go showed that CyA also inhibits eNOS activity. Second, although ET-1 levels were not elevated by CyA treatment, ETA Rc protein expression in the TAo was significantly increased with no concomitant change in ETB Rc protein expression. ETA Rc activation results in vasoconstriction, whereas ETB Rc on endothelial cells results in vasodilation. Therefore, an increased ETA Rc-to-ETB Rc ratio results in greater vasoconstriction. Thus, CyA results in greater sensitivity to ET-1–induced vasospasm. Hunley and colleagues36Go showed in a rodent model that CyA-induced renal dysfunction was abrogated after treatment with BQ123, an ETA Rc antagonist. Takeda and colleagues37Go observed a similar finding in mesangial cells where ET-1 antagonism protected against CyA-induced injury. Therefore, ETA Rc up-regulation may be a common pathway by which CyA results in injury in various cell types. CyA also resulted in a higher SNP ED50 compared with the other treatment groups, indicating impaired cyclic guanosine monophosphate-dependent smooth muscle cell relaxation. The study by Khalil and colleagues34Go reinforces our observations. They demonstrated that CyA impaired both endothelial-dependent and independent vasodilation. Previous studies by Diederich and colleagues29Go and Galle38Go have suggested that CyA treatment increases free radical production. In comparison with our investigations, the study by Diederich and colleagues29Go used an elevated dose of CyA (25 mg/kg), and the study by Galle and colleagues38Go was performed on isolated vascular rings and not in an in vivo model. Our study confirmed that oxidative injury (increased 8-isoprostane levels) occurred after even low-normal CyA exposure in an in vivo model. Oxidative injury may also account for the smooth muscle dysfunction observed after CyA therapy. In addition, oxygen radicals can inhibit NO production, worsening vascular homeostasis. Proinflammatory cytokines can aggravate oxidative injury and represent a possible mechanism of injury after either CyA or Hcort exposure. However, we found no significant changes in myocardial levels of either transforming growth factor-{alpha} or tumor necrosis factor-β, suggesting that a heightened inflammatory response is not the cause of our observed derangements. Additional markers of inflammation need to be assessed to confirm this conclusion.

Corticosteroids are also associated with impaired vasomotor function. Unlike CyA, Hcort did not impair endothelial-dependent vascular dilatation. However, Hcort did result in a similar decrease in eNOS protein expression, indicating that impaired NO regulation seen with CyA may be due to impaired enzyme function in addition to decreased protein expression. There was no impairment in endothelial-independent vasodilation with Hcort therapy. Hcort treatment did result in increased sensitivity to ET-1. Hcort exposure increased ETA Rc expression with no change in ETB Rc expression. Unlike CyA, Hcort treatment did not result in oxidative injury. Thus, we speculate that CyA treatment results in functional uncoupling of the eNOS enzyme producing free radicals instead of NO. Furthermore, functional uncoupling of eNOS by CyA may explain why similar reductions in protein expression did not result in impaired endothelial vasodilation with Hcort. Transplant recipients are commonly given both a corticosteroid and CyA. We demonstrated that Hcort therapy aggravates CyA-induced smooth muscle dysfunction as indicated by worsened endothelial-independent vasorelaxation and heightened sensitivity to ET-1 vasospasm.

We have made the following novel observations (Go Table 1):

1. CyA results in alteration of both NO and ET-1 regulation, leading to impairment of vasodilation and increased sensitivity to vasospasm.
2. Hcort results in decreased eNOS expression and increased ETA Rc expression, resulting in increased sensitivity to vasospasm.
3. CyA results in direct oxidative injury to the endothelium.
4. Corticosteroid treatment aggravates CyA-induced vasomotor dysfunction.


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  		Table 1 Summary of vascular effects of cyclosporine A, hydrocortisone, and cyclosporine + hydrocortisone
 
Our findings suggest possible treatment strategies for improving vasomotor function in patients receiving standard immunosuppression. An effective strategy must include ET-1 antagonism in addition to functional coupling of eNOS. This may be achieved by using an ET-1 antagonist (eg, bosentan) and tetrahydrobiopterin, an essential eNOS cofactor, for stabilizing the eNOS complex and reducing free radical production. In the case of corticosteroids, an effective strategy must include ET-1 antagonism and an NO donor. This may be achieved by using bosentan and L-arginine, an NO donor, to counterbalance the increased sensitivity to ET-1. Our findings provide potential mechanisms for the development of CyA and corticosteroid-induced hypertension, as well as a direct mechanism by which CyA may lead to transplant vasculopathy. Further studies will delineate the putative beneficial effects of our proposed treatment strategies.


   Conclusions
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 Conclusions
References
 
The present study was designed to investigate the direct effect of our treatment groups on vascular function in the absence of an immune response or a period of ischemia/reperfusion. Clearly, the effects of the latter 2 variables will need further assessment in a heterotopic transplant model. In addition, we evaluated changes in aortic tissue as opposed to coronary arteries. Although the responses are likely consistent, it is possible that both CyA and Hcort exert differential effects on coronary vasculature than seen in the TAo.


   Footnotes
 
Supported by the Heart and Stroke Foundation of Ontario (Grant NA 5868), Canadian Institutes for Health Research, Thoracic Surgery Foundation for Research and Education, Tailored Advanced Collaborative Training in Cardiovascular Science, and Physician Services Incorporated Foundation Grant for Research Fellows. Dr Ramzy is a Research Fellow of the Thoracic Surgery Foundation for Research and Education, Policy Studies Institute, and Tailored Advanced Collaborative Training in Cardiovascular Sciences. Dr Rao is a Canadian Institutes of Health Research New Investigator.

Manuscript accepted for the C. Walton Lillehei Resident Forum Session at the Annual Meeting of the American Association for Thoracic Surgery.

Read at the Eighty-seventh Annual Meeting of The American Association for Thoracic Surgery, Washington, DC, May 5-9, 2007.


   References
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 Conclusions
 References
 

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ANN THORAC SURG ASIAN CARDIOVASC THORAC ANN EUR J CARDIOTHORAC SURG
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