Allograft vasculopathyBcl-2–mediated inhibition of apoptosis in rat cardiac allografts worsens development of graft coronary artery disease☆
Section snippets
Animals
Adult male ACI (RT-1a) and PVG (RT-1c) rats, weighing between 200 and 250g, were purchased from Harlan Sprague-Dawley (Indianapolis) and housed in the animal care facilities at Stanford University Medical Center (Stanford, CA). They were kept under standard temperature, humidity and timed lighting conditions and were provided rat chow and water ad libitum. Animals were treated in a humane manner, in compliance with the Guide for the Care and Use of Laboratory Animals, prepared by the Institute
Bcl-2 expression
Treatment of donor hearts ex vivo with adenovirus-expressing Bcl-2 resulted in upregulation of this gene product as measured by western blot analysis on POD 4. Expression in the null virus–treated hearts was similar to the baseline levels seen in native, non-transplanted hearts (Figure 1). Densitometric analysis of Bcl-2 bands on western blots demonstrated significant differences in protein expression (AdvBcl-2, 93,765 ± 18,538; AdvNull, 48,802 ± 21,906; native hearts, 42,770 ± 9,159) Units
Discussion
Prevention of apoptosis has emerged as a potential strategy for the treatment of acute allograft rejection. Excessive programmed cell death has been implicated in several disease processes such as ischemia–reperfusion injury, autoimmune disorders and acute rejection of transplanted organs.15 Treatment of these disorders with anti-apoptotic therapy, however, represents something of a “double-edged sword.” For example, interruption of apoptosis may interfere with the normal mechanism by which
Conclusions
AdvBcl-2 treatment of cardiac allografts in this rodent model resulted in a reduction of apoptosis that did not significantly prolong short-term allograft survival. Graft coronary artery disease, however, was exacerbated, possibly due to the lack of vascular smooth muscle cell apoptosis during vessel remodeling. Our study has highlighted an important long-term concern regarding the use of anti-apoptotic therapy as a potential adjunct to current modes of immunosuppression in cardiac
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Cited by (4)
Expression of HSPA12B in acute cardiac allograft rejection in rats
2015, Pathology Research and PracticeCitation Excerpt :Thus, caspase-3 activation is considered to be essential to execution of apoptosis. In addition, several early studies decreased apoptosis through inhibiting caspase-3 activity in acute cardiac allograft rejection, which significantly prolong allografts survival [39,40,43–46]. As shown in this study (Fig. 4A and B), active caspase-3 was initially increased at day 3, and significantly elevated up at days 5–7 post-transplant parallelling with HSPA12B expression in allografts, which is not shown in isografts.
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Supported by the Roche Laboratories Surgical Scientist Scholarship from the American Society of Transplant Surgeons and the Ralph and Marian Falk Foundation for Cardiovascular Research.