Cardiomyocyte-specific Bcl-2 overexpression attenuates ischemia-reperfusion injury, immune response during acute rejection, and graft coronary artery disease

Masashi Tanaka, Susumu Nakae, Raya D. Terry, Golnaz K. Mokhtari, Feny Gunawan, Leora B. Balsam, Hideaki Kaneda, Theo Kofidis, Philip S. Tsao, Robert C. Robbins

Research output: Contribution to journalArticlepeer-review

61 Scopus citations

Abstract

After cardiac transplantation, graft damage occurs secondary to ischemia-reperfusion injury and acute rejection. This damage ultimately leads to the development of graft coronary artery disease (GCAD), which limits long-term graft survival. Apoptosis is directly involved in graft injury, contributing to the development of GCAD. To assess the role of the antiapoptotic factor Bcl-2 in the process of GCAD, we transplanted hearts from FVB transgenic mice overexpressing human Bcl-2 under the control of α-myosin heavy chain promoter into allogenic C57BL/6 mice. Bcl-2 overexpression led to reduced cytochrome c-mediated caspase-9-dependent cardiomyocyte apoptosis and local inflammation (neutrophil infiltration and proinflammatory cytokine production) in cardiac allografts during ischemia-reperfusion injury and also led to reduced immune responses (inflammatory cell infiltration, production of TH1 cytokines and chemokines, and expression of adhesion molecules) during acute and chronic rejection without affecting host CD4+ and CD8+ cell responses in the spleen. Thus, local Bcl-2 expression directly contributes to the modulation of local immune responses in allograft rejection, resulting in attenuated GCAD. In conclusion, our findings suggest that the modulation of Bcl-2 expression by pharmacologic up-regulation or gene transfer may be of clinical benefit in the short- and long-term function of cardiac allografts.

Original languageEnglish (US)
Pages (from-to)3789-3796
Number of pages8
JournalBlood
Volume104
Issue number12
DOIs
StatePublished - Dec 1 2004
Externally publishedYes

ASJC Scopus subject areas

  • Biochemistry
  • Immunology
  • Hematology
  • Cell Biology

Fingerprint

Dive into the research topics of 'Cardiomyocyte-specific Bcl-2 overexpression attenuates ischemia-reperfusion injury, immune response during acute rejection, and graft coronary artery disease'. Together they form a unique fingerprint.

Cite this