Upregulation of heme oxygenase-1 during the development of accelerated graft vascular disease after clinical heart transplantation

Abstract

Ischemia induced oxidative stress may not only be important in the early posttransplant period, but also during the development of graft vascular disease (GVD) after heart transplantation. Oxidative stress leads to upregulation of heme oxygenase (HO)-1 as a result of activation of the transcription factor hypoxia inducible factor (HIF)-1 . HO-1 is an antioxidant enzym, with anti-apoptotic properties. It is also described that in vitro HO-1 production is regulated by transforming growth factor (TGF), a cytokine that plays a role in the development of GVD after heart transplantation. We hypothesize that HO-1 is involved in the development of GVD, a condition characterized by unrestrained proliferation of smooth muscle cells. To test this hypothesis, we measured mRNA levels of HIF-1 , HO-1 and TGFin biopsies from patients with (n 14) and without (n 13) signs of acceleratd GVD (at one year) after heart transplantation. We found significantly higher HO-1 and TGFmRNA expression levels in biopsies from patients with GVD (p 0.02 and p 0.04, Mann Whitney, figure). Furthermore, in GVD positive, but not in GVD negative patients, a significant strong correlation was found between HIF-1 and HO-1 (rs 0.92, p 0.0001), between HIF-1 and TGF(rs 0.74, p 0.0026) and between HO-1 and TGF(rs 0.65, p 0.011). Our results show that, in accordance with our hypothesis, HO-1 is involved in the development of GVD after heart transplantation. We suggest that TGFinitiates GVD resulting in ischemic damage and thus in HIF-1 induced production of HO-1. HO-1 prevents apoptosis, allowing smooth muscle cells to proliferate, subsequently leading to intima thickening and accelerated graft vascular disease.