Yamani Mohamad H, Cook Daniel J, Rodriguez E Rene, Thomas Dawn M, Gupta Sandeep, Alster Joan, Taylor David O, Hobbs Robert, Young James B, Smedira Nicholas, Starling Randall C
Department of Cardiovascular Medicine, The Cleveland Clinic Foundation, Cleveland, Ohio 44195, USA.
J Heart Lung Transplant. 2006 Nov;25(11):1283-9. doi: 10.1016/j.healun.2006.09.012. Epub 2006 Oct 17.
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.
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 > or =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.
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.
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.
血管紧张素II 1型受体（AGTR1）在细胞免疫过程的调节中起重要作用。我们推测，在人类心脏移植中，反复急性排斥反应与AGTR1基因表达增加有关。
我们确定了一组14例发生反复急性细胞排斥反应（RAR）的心脏移植受者，反复急性细胞排斥反应定义为连续三次急性排斥反应发作（分级≥3A）。这些患者与一个对照组（n = 15）进行匹配。在移植后1周时，测量对照组心脏活检标本中AGTR1的mRNA基因表达。在RAR组中，于基线、每次排斥反应发作时以及排斥反应消退后，连续测定AGTR1 mRNA。还评估了血管紧张素转换酶（ACE）多态性。
对照组和RAR组在基线时的AGTR1 mRNA表达相似。与基线相比，RAR组在第一次排斥反应发作时AGTR1的mRNA表达显著增加（9倍，p < 0.001），在第二次发作时进一步增加（12倍，p < 0.001），并在第三次发作时达到峰值（35倍，p < 0.001）。排斥反应消退后，AGTR1表达显著降低（p < 0.001），但仍高于基线水平（6倍，p < 0.001）。两组之间的ACE多态性无差异。与对照组相比，在平均51.5±12个月的随访期内，RAR患者发生高血压、糖尿病、慢性肾功能不全和移植血管病变的发生率增加。
这是第一份描述AGTR1 mRNA表达因反复细胞排斥反应而增加的报告。AGTR1的上调对排斥反应治疗有反应，但不能完全恢复，这一现象可能潜在地解释了排斥反应与后续临床结局之间的联系。
