Rapamycin Reverses Chronic Graft Vascular Disease in a Novel Cardiac Allograft Model

Poston, Robert; Billingham, Margaret E.; Hoyt, E. Grant; Pollard, Jeffrey D.; Shorthouse, R.; Morris, Randall E.; Robbins, Robert C.

doi:10.1161/01.cir.100.1.67

Cited by 150 publications

(76 citation statements)

References 16 publications

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“…Together, these experiments provide evidence that mTOR regulates rapid changes in surface phenotype of specialized cells, in addition to its well known roles in cell cycle progression and cell growth (3,7). It is possible that this action may account for some of the beneficial effects of rapamycin in pathologic processes that are influenced by monocytes or other cells in which this mechanism may operate, such as angiogenesis and restenosis (37,38).…”

Section: Rapid Synthesis Of Upar In Monocytes Adherent To P-selectin mentioning

confidence: 89%

Cell adhesion regulates gene expression at translational checkpoints in human myeloid leukocytes

Mahoney

Weyrich

Dixon

et al. 2001

Proc. Natl. Acad. Sci. U.S.A.

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Engagement of adhesion molecules on monocytes and other myeloid leukocytes, which are effector cells of the innate immune system, not only tethers the leukocytes in place but also transmits outside-in signals that induce functional changes and alter gene expression. We found that a subset of mRNAs that are induced or amplified by adhesion of human monocytes to P-selectin via its surface ligand, P-selectin glycoprotein 1, have characteristics that suggest specialized translational control. One of these codes for urokinase plasminogen activator receptor (UPAR), a critical surface protease receptor and regulator of cell adhesion and migration. Although UPAR transcripts are induced by adhesion, rapid synthesis of the protein uses constitutive mRNA without a requirement for new transcription and is regulated by mammalian target of rapamycin, demonstrating new biologic roles for the signaldependent translation pathway controlled by this intracellular kinase. The synthesis of UPAR in monocytic cells is also regulated by eukaryotic translation initiation factor 4E, a second key translational checkpoint, and phosphorylation of eukaryotic translation initiation factor 4E is induced by adhesion of monocytes to Pselectin. Translationally controlled display of UPAR by monocytes confers recognition of the matrix protein, vitronectin. Adhesiondependent signaling from the plasma membrane to translational checkpoints represents a previously unrecognized mechanism for regulating surface phenotype that may be particularly important for myeloid leukocytes and other cells that are specialized for rapid inflammatory and vascular responses.

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Section: Rapid Synthesis Of Upar In Monocytes Adherent To P-selectin mentioning

confidence: 89%

Cell adhesion regulates gene expression at translational checkpoints in human myeloid leukocytes

Mahoney

Weyrich

Dixon

et al. 2001

Proc. Natl. Acad. Sci. U.S.A.

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“…Survival curve was generated using the Kaplan-Meier method and compared using the longrank (Mantel-Cox) test. *P ϭ 0.0376; 2 ϭ 4.323 In addition, Poston et al (28) suggested that rapamycin stabilizes and possibly reverses chronic graft vascular disease in a cardiac allograft model. This evidence supported the introduction in the clinical setting of rapamycin-mediated vascular stent for coronary artery disease to reduce the incidence of poststent stenosis (29).…”

Section: Discussionmentioning

confidence: 99%

Rapamycin for Treatment of Chronic Allograft Nephropathy in Renal Transplant Patients

Stallone

Infante

Schena³

et al. 2005

Journal of the American Society of Nephrology

113

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Chronic allograft nephropathy (CAN) represents the main cause of renal allograft loss after 1 yr of transplantation. Calcineurin inhibitor (CNI) use is associated with increased graft expression of profibrotic cytokines, whereas rapamycin inhibits fibroblast proliferation. The aim of this randomized, prospective, open-label, single-center study was to evaluate the histologic and clinical effect of rapamycin on biopsy-proven CAN. Eighty-four consecutive patients who had biopsy-proven CAN and received a transplant were randomized to receive either a 40% CNI reduction plus mycophenolate mofetil (group 1; 50 patients) or immediate CNI withdrawal and rapamycin introduction with a loading dose of 0.1 mg/kg per d and a maintaining dose aiming at through levels of 6 to 10 ng/ml (group 2; 34 patients). The follow-up period was 24 mo. At the end of follow-up, 25 patients (group 1, 10 patients; group 2, 15 patients) underwent a second biopsy. CAN lesions were graded according to Banff criteria. ␣-Smooth muscle actin (␣-SMA) protein expression was evaluated in all biopsies as a marker of fibroblast activation. Graft function and Banff grading were superimposable at randomization. Graft survival was significantly better in group 2 (P ‫؍‬ 0.0376, 2 ‫؍‬ 4.323). CAN grading worsened significantly in group 1, whereas it remained stable in group 2. After 24 mo, all group 1 biopsies showed an increase of ␣-SMA expression at the interstitial and vascular levels (P < 0.001); on the contrary, ␣-SMA expression was dramatically reduced in group 2 biopsies (P ‫؍‬ 0.005). This study demonstrates that rapamycin introduction/CNI withdrawal improves graft survival and reduces interstitial and vascular ␣-SMA expression, slowing down the progression of allograft injury in patients with CAN.

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“…In contrast, another study failed to obtain a difference between renal transplant recipients with and without diabetes in terms of graft loss [19]. It could be likely, that either a follow-up period of 10 years is too short or our immunosuppressive protocol per se delays to a certain extent the development of atherosclerosis in coronary arteries [15,20,21,22].…”

Section: Discussionmentioning

confidence: 98%

The impact of diabetes mellitus at the time of heart transplantation on long-term survival

Czerny

Şahin

Fasching³

et al. 2002

Diabetologia

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Aims/hypothesis. To analyse the impact of diabetes mellitus (DM) at the time of heart transplantation on long-term survival and incidence of transplant coronary artery disease (TxCAD). Methods. We analysed 773 consecutive adult heart transplant recipients who underwent primary heart transplantation from May 1986 until December 2000. The cohort consisted of 140 patients with diabetes mellitus (with DM, men 82%) and 633 patients without (wo DM, men 84%) diabetes mellitus at the time of transplantation. The patients were documented as to survival and incidence of TxCAD. Results. Patients with diabetes mellitus were older compared to those without diabetes mellitus (with DM 54.9±6.8a vs wo DM 49.7±10.8a; p=0.0001), they had a higher incidence of ischaemic cardiomyopathy prior to transplantation (with DM 52% vs wo DM 30%; p=0.0001), but reduced long-term survival (10 year survival: with DM 40% vs wo DM 58%; logrank=0.025). Surprisingly, the incidence of transplant coronary artery disease (TxCAD) was comparable at 10 years (with DM 28% vs wo DM 22%; logrank=0.625). In multivariate Cox proportional hazard analysis, diabetes mellitus present at the time of heart transplantation (HR 1.594; 95%CI 1.009-2.518; p=0.045), but not age (HR 0.990; 95%CI 0.965-1.014; p=0.404) was an independent predictor affecting long-term survival. Conclusion/interpretation. The presence of diabetes mellitus at the time of heart transplantation adversely affects long-term patient survival, but does not predict the occurrence of transplant coronary artery disease. The definite mechanisms of adverse survival primarily seem to relate to generally impaired global organ function. Despite a less favourable long-term outcome, our data still justify heart transplantation in end-stage heart failure patients with diabetes mellitus.

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Rapamycin Reverses Chronic Graft Vascular Disease in a Novel Cardiac Allograft Model

Cited by 150 publications

References 16 publications

Cell adhesion regulates gene expression at translational checkpoints in human myeloid leukocytes

Cell adhesion regulates gene expression at translational checkpoints in human myeloid leukocytes

Rapamycin for Treatment of Chronic Allograft Nephropathy in Renal Transplant Patients

The impact of diabetes mellitus at the time of heart transplantation on long-term survival

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