BACKGROUND: Chronic rejection in transplanted hearts or cardiac allograft vasculopathy (CAV) is the leading cause of late death among heart transplant recipients. Strategies to control CAV traditionally have focused on lymphocyte functions. We hypothesized that D-4F, an apoA-I mimetic peptide with potent anti-inflammatory/antioxidant properties, will attenuate CAV. METHODS: We used a previously characterized murine model of CAV. B6.C-H2 hearts were heterotopically transplanted into C57BL/6 mice. Recipient mice were treated with either 20 microg of D-4F or carrier daily. Donor hearts were harvested on day 24 after transplantation. RESULTS: Treatment of recipients with D-4F reduced the severity of intimal lesions (62.5+/-3.4% vs. 31.1+/-8.7%, P<0.009). Treatment also resulted in a decrease in the number of graft-infiltrating CD4 and CD8 lymphocytes and CXCR3+ T-lymphocyte subsets. Heme oxygenase-1 (HO-1) gene transcript in the donor hearts was up-regulated with D-4F treatment, and HO-1 blockade partially reversed the beneficial effects of D-4F. In vitro studies showed that D-4F reduced allogeneic T-lymphocyte proliferation and effector cytokine production. These processes were HO-1 independent. CONCLUSION: This study suggests that D-4F, a prototypical apoA-I mimetic peptide, is effective in controlling CAV via induction of HO-1 in the graft and a direct effect on T-lymphocyte function. This class of peptides with anti-inflammatory/antioxidant properties provides a novel strategy in the treatment of CAV.
BACKGROUND: Chronic rejection in transplanted hearts or cardiac allograft vasculopathy (CAV) is the leading cause of late death among heart transplant recipients. Strategies to control CAV traditionally have focused on lymphocyte functions. We hypothesized that D-4F, an apoA-I mimetic peptide with potent anti-inflammatory/antioxidant properties, will attenuate CAV. METHODS: We used a previously characterized murine model of CAV. B6.C-H2 hearts were heterotopically transplanted into C57BL/6 mice. Recipient mice were treated with either 20 microg of D-4F or carrier daily. Donor hearts were harvested on day 24 after transplantation. RESULTS: Treatment of recipients with D-4F reduced the severity of intimal lesions (62.5+/-3.4% vs. 31.1+/-8.7%, P<0.009). Treatment also resulted in a decrease in the number of graft-infiltrating CD4 and CD8 lymphocytes and CXCR3+ T-lymphocyte subsets. Heme oxygenase-1 (HO-1) gene transcript in the donor hearts was up-regulated with D-4F treatment, and HO-1 blockade partially reversed the beneficial effects of D-4F. In vitro studies showed that D-4F reduced allogeneic T-lymphocyte proliferation and effector cytokine production. These processes were HO-1 independent. CONCLUSION: This study suggests that D-4F, a prototypical apoA-I mimetic peptide, is effective in controlling CAV via induction of HO-1 in the graft and a direct effect on T-lymphocyte function. This class of peptides with anti-inflammatory/antioxidant properties provides a novel strategy in the treatment of CAV.
Authors: Mary E Ziegler; Tingchao Chen; James F LeBlanc; Xuelian Wei; David W Gjertson; Ker-Chau Li; Mazdak A Khalighi; Charles R Lassman; Jeffrey L Veale; H Albin Gritsch; Elaine F Reed Journal: Transplantation Date: 2011-08-27 Impact factor: 4.939
Authors: Brian J Van Lenten; Mohamad Navab; G M Anantharamaiah; Georgette M Buga; Srinivasa T Reddy; Alan M Fogelman Journal: Curr Opin Investig Drugs Date: 2008-11
Authors: Ali Javaheri; Maria Molina; Payman Zamani; Amrith Rodrigues; Eric Novak; Susan Chambers; Patricia Stutman; Wilhelmina Maslanek; Mary Williams; Scott M Lilly; Peter Heeger; Mohamed H Sayegh; Anil Chandraker; David M Briscoe; Kevin P Daly; Randall Starling; David Ikle; Jason Christie; J Eduardo Rame; Lee R Goldberg; Jeffrey Billheimer; Daniel J Rader Journal: J Heart Lung Transplant Date: 2016-07-15 Impact factor: 10.247
Authors: Brian J Van Lenten; Alan C Wagner; Chun-Ling Jung; Piotr Ruchala; Alan J Waring; Robert I Lehrer; Andrew D Watson; Susan Hama; Mohamad Navab; G M Anantharamaiah; Alan M Fogelman Journal: J Lipid Res Date: 2008-07-11 Impact factor: 5.922