Restoration of the cAMP second messenger pathway enhances cardiac preservation for transplantation in a heterotopic rat model

D. Pinsky, M. Oz, H. Liao, S. Morris, J. Brett, R. Sciacca, M. Karakurum, M. Van Lookeren Campagne, J. Platt, R. Nowygrod, S. Koga, David Stern

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Abstract

Current organ preservation strategies subject graft vasculature to severe hypoxia (PO2 ~ 20 Torr), potentially compromising vascular function and limiting successful transplantation. Previous work has shown that cAMP modulates endothelial cell (EC) antithrombogenicity, barrier function, and leukocyte/EC interactions, and that hypoxia suppresses EC cAMP levels. To explore the possible benefits of cAMP analogs/agonists in organ preservation, we used a rat heterotopic cardiac transplant model; dibutyryl cAMP added to preservation solutions was associated with a time- and dose-dependent increase in the duration of cold storage associated with successful graft function. Preservation was also enhanced by 8-bromo-cAMP, the S(p) isomer of adenosine 3',5'monophosphorothioate, and types III (indolidan) and IV (rolipram) phosphodiesterase inhibitors. Neither butyrate alone nor 8- bromoadenosine were effective, and the cAMP-dependent protein kinase antagonist R(p) isomer of adenosine 3',5'monophosphorothioate prevented preservation enhancement induced by 8-bromo-cAMP. Grafts stored with dibutyryl cAMP demonstrated a 5.5-fold increase in blood flow and a 3.2-fold decreased neutrophil infiltration after transplantation. To explore the role of cAMP in another cell type critical for vascular homeostasis, vascular smooth muscle cells were subjected to hypoxia, causing a time-dependent decline in cAMP levels. Although adenylate cyclase activity was unchanged, diminished oxygen tensions were associated with enhanced phosphodiesterase activity (59 and 30% increase in soluble types III and IV activity, respectively). These data suggest that hypoxia or graft ischemia disrupt vascular homeostasis, at least in part, by perturbing the cAMP second messenger pathway. Supplementation of this pathway provides a new approach for enhancing cardiac preservation, promoting myocardial function, and maintaining vascular homeostatic properties.

Original languageEnglish (US)
Pages (from-to)2994-3002
Number of pages9
JournalJournal of Clinical Investigation
Volume92
Issue number6
DOIs
StatePublished - Jan 1 1993

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Second Messenger Systems
Heart Transplantation
Blood Vessels
Transplants
Organ Preservation
8-Bromo Cyclic Adenosine Monophosphate
Endothelial Cells
indolidan
Homeostasis
Transplantation
Rolipram
Cell Hypoxia
Phosphodiesterase Inhibitors
Neutrophil Infiltration
Butyrates
Phosphoric Diester Hydrolases
Cyclic AMP-Dependent Protein Kinases
Vascular Smooth Muscle
Adenylyl Cyclases
Cell Communication

All Science Journal Classification (ASJC) codes

  • Medicine(all)

Cite this

Restoration of the cAMP second messenger pathway enhances cardiac preservation for transplantation in a heterotopic rat model. / Pinsky, D.; Oz, M.; Liao, H.; Morris, S.; Brett, J.; Sciacca, R.; Karakurum, M.; Van Lookeren Campagne, M.; Platt, J.; Nowygrod, R.; Koga, S.; Stern, David.

In: Journal of Clinical Investigation, Vol. 92, No. 6, 01.01.1993, p. 2994-3002.

Research output: Contribution to journalArticle

Pinsky, D, Oz, M, Liao, H, Morris, S, Brett, J, Sciacca, R, Karakurum, M, Van Lookeren Campagne, M, Platt, J, Nowygrod, R, Koga, S & Stern, D 1993, 'Restoration of the cAMP second messenger pathway enhances cardiac preservation for transplantation in a heterotopic rat model', Journal of Clinical Investigation, vol. 92, no. 6, pp. 2994-3002. https://doi.org/10.1172/JCI116922
Pinsky, D. ; Oz, M. ; Liao, H. ; Morris, S. ; Brett, J. ; Sciacca, R. ; Karakurum, M. ; Van Lookeren Campagne, M. ; Platt, J. ; Nowygrod, R. ; Koga, S. ; Stern, David. / Restoration of the cAMP second messenger pathway enhances cardiac preservation for transplantation in a heterotopic rat model. In: Journal of Clinical Investigation. 1993 ; Vol. 92, No. 6. pp. 2994-3002.
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AU - Van Lookeren Campagne, M.

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AU - Nowygrod, R.

AU - Koga, S.

AU - Stern, David

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