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

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 ␣-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 T H 1 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.

Down‐regulation of CD68 after simvastatin treatment of isoproterenol‐induced myocardial infarction in rats

“…Hypertension produces collagen deposition, changes referred to as myocardial fibrosis, which leads to depressed myocardial performance (Bu et al, 2008). Some studies indicated that ISO-induced acute myocardial infarction after ischemia is caused by myocardial hyperactivity and coronary hypertension (Yeager and Iams, 1981), the inflammatory response (Steffens et al, 2009) and cell apoptosis (Tanaka et al, 2004). In this study, the reduced inflammatory cellular infiltration, myocardial necrosis, and fibrosis in SIM pre-treated rats (group IV) confirmed the cardio-protective effect of SIM.…”

The protective effects of emulsified isoflurane on myocardial ischemia and reperfusion injury in rats

“…*P \ 0.05, **P \ 0.01 vs. sham group; P \ 0.05, P \ 0.01 vs. CON group; à P \ 0.05, àà P \ 0.01 vs. IL group overexpression of Bcl-2 in cardiomyocytes suppresses I/R injury in transgenic mice. 27 By contrast, pro-apoptotic Bax serves as an inducer of apoptosis to counteract the action of Bcl-2, and the ratio of Bcl-2/Bax determines cell survival or death. 28 A limited number of previous studies have shown that isoflurane may be capable of protecting hearts against apoptosis.…”

Indices of Apoptosis Activation After Blood Cardioplegia and Cardiopulmonary Bypass

“…It is still widely controversial whether the phosphorylation of Bcl-2 is a pro-apoptotic or anti-apoptotic event. The Bcl-2 family of proteins regulates apoptosis by controlling mitochondrial permeability and the release of cytochrome c. 20 The anti-apoptotic proteins of Bcl-2 reside in the outer mitochondrial wall and inhibit cytochrome c release. Figure 6 provides a summary of possible apoptosis activation pathways after CBC/CPB observed.…”