Antioxidant properties of pioglitazone limit nicotinamide adenine dinucleotide phosphate hydrogen oxidase and augment superoxide dismutase activity in cardiac allotransplantation

Abstract

Many non-immunologic factors contribute to the development of cardiac allograft vasculopathy (CAV), chief among them being ischemia-reperfusion injury associated with oxidative stress. We hypothesized that pioglitazone, a peroxisome proliferator-activated receptor (PPAR)-γ agonist, could attenuate graft oxidant stress in cardiac transplantation. Experiments were performed using a murine heterotopic cardiac allotransplantation model. Pioglitazone was administered to recipients once daily, beginning 1 day before transplantation. At 4 hours after transplantation, pioglitazone significantly reduced the expression of endothelial cell adhesion receptors and infiltration of polymorphonuclear leukocytes (PMNs). The anti-oxidant balance in pioglitazone-treated cardiac allografts was significantly bolstered by reduced nicotinamide adenine dinucleotide phosphate hydrogen (NADPH) oxidase (Nox1 and p22(phox) sub-units) activity and preservation of manganese superoxide dismutase (SOD) activity, resulting in the mitigation of oxidative damage at the level of lipids, proteins, and DNA. At 7 days after transplantation, PPAR-γ was significantly up-regulated by pioglitazone, but nuclear factor-κB and inducible nitric oxide synthase were significantly down-regulated. A concomitant reduction of inflammatory cytokines and chemokines and graft leukosequestration was noted. Pioglitazone consequently prolonged cardiac allograft survival and attenuated CAV development. In vitro experiments demonstrated that pioglitazone decreased transendothelial PMN migration, NADPH oxidase activity, and loss of SOD activity in PMNs and endothelial cells. Pioglitazone can suppress the oxidative stress and damage and can stimulate antioxidant capacity in cardiac allografts after transplantation. Mitigation of graft oxidant stress could be an important mechanism through which pioglitazone confers benefit after cardiac transplantation.