Increased Expression of Angiotensin II Type 1 Receptor (AGTR1) in Heart Transplant Recipients With Recurrent Rejection

Background: Angiotensin II receptor sub-type 1 (AGTR1) plays an important role in the regulation of the cellular immune process. We hypothesized that recurrent acute rejection is associated with increased gene expression of AGTR1 in human heart transplantation. Methods: We identified a group of 14 heart transplant recipients who had recurrent acute cellular rejection (RAR), defined as three consecutive episodes of acute rejection (Grade ≥3A). These patients were matched to a control group (n = 15). mRNA gene expression of AGTR1 was measured in heart biopsy specimens of controls at 1 week post-transplant. AGTR1 mRNA was determined serially in the RAR group at baseline, each rejection episode, and after resolution of rejection. Angiotensin-converting enzyme (ACE) polymorphism was also evaluated. Results: Both the control and RAR groups had similar mRNA AGTR1 expression at baseline. Compared with baseline, the RAR group had significantly increased mRNA expression of AGTR1 at the first episode of rejection (9-fold, p < 0.001), which increased further at the second episode (12-fold, p < 0.001) and peaked at the third episode (35-fold, p < 0.001). After resolution of rejection, AGTR1 expression was decreased significantly (p < 0.001), but remained elevated above baseline (6-fold, p < 0.001). No difference in ACE polymorphism was noted between the two groups. Compared with controls, the RAR patients had an increased incidence of hypertension, diabetes mellitus, chronic renal insufficiency and transplant vasculopathy during a mean follow-up period of 51.5 ± 12 months. Conclusions: This is the first report to describe increased mRNA expression of AGTR1 in response to recurrent cellular rejection. Up-regulation of AGTR1 responds to treatment of rejection but not to complete recovery, a phenomenon that may potentially explain the link between rejection and subsequent clinical outcome.