Increased Expression of Angiotensin II Type 1 Receptor (AGTR1) in Heart Transplant Recipients With Recurrent Rejection Mohamad H. Yamani, MD, a Daniel J. Cook, PhD, b E. Rene Rodriguez, MD, c Dawn M. Thomas, MS, b Sandeep Gupta, MD, b Joan Alster, PhD, d David O. Taylor, MD, a Robert Hobbs, MD, a James B. Young, MD, e Nicholas Smedira, MD, f and Randall C. Starling, MD, MPH a 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. J Heart Lung Transplant 2006;25:1283–9. Copyright © 2006 by the International Society for Heart and Lung Transplantation. Several experimental studies have provided insights into the immunoregulatory function of the renin–angio- tensin system (RAS). 1–4 We have previously shown that the angiotensin II receptor sub-type 1 (AGTR1) plays a key role in the pathogenesis of transplant vasculopa- thy, 5 and its role in the pathogenesis of renal vascular rejection has been recently explored. 6 AGTR1 activa- tion stimulates multiple intracellular signaling cascades that regulate several processes, including cellular pro- liferation, fibrosis, smooth muscle cell hyperplasia, ex- tracellular matrix accumulation, pro-inflammatory re- sponses and immune modulation. 7–9 In their study, Nataraj et al elucidated a molecular mechanism for the RAS-mediated regulation of cellular immune response in the heart transplant model. They suggested that angio- tensin II (Ang II) may function as an autocrine factor for promoting T-cell proliferation. 4 Immunosuppressive treatment was shown to alleviate Ang II–induced organ damage, a finding that sheds light on the vital interac- tion between immune mechanisms and RAS. 10,11 Angio- tensin receptor blockade was also shown to be effective in reducing the risk of chronic rejection in animal transplant models. 12 The aforementioned investigations have prompted us to evaluate the myocardial mRNA gene expression of AGTR1 in patients with recurrent acute cellular rejection. We also evaluated the impact, if any, of recipient angiotensin-converting enzyme (ACE) polymorphism on rejection. From the a Department of Cardiovascular Medicine, b Allogen Labo- ratory, c Department of Anatomic Pathology, d Department of Bio- statistics, e Division of Medicine and f Department of Cardiothoracic Surgery, Kaufman Center for Heart Failure, The Cleveland Clinic Foundation, Cleveland, Ohio. Submitted June 7, 2006; revised August 24, 2006; accepted Sep- tember 9, 2006. Reprint requests: Mohamad H. Yamani, MD, Department of Cardio- vascular Medicine, The Cleveland Clinic Foundation, F25, 9500 Euclid Avenue, Cleveland, OH 44195. Telephone: 216-444-2755. Fax: 216- 444-3407. E-mail: yamanim@ccf.org Copyright © 2006 by the International Society for Heart and Lung Transplantation. 1053-2498/06/$–see front matter. doi:10.1016/ j.healun.2006.09.012 1283