Francois Helene, Athirakul Krairerk, Howell David, Dash Rajesh, Mao Lan, Kim Hyung-Suk, Rockman Howard A, Fitzgerald Garret A, Koller Beverly H, Coffman Thomas M
Department of Medicine, Duke University and Durham VA Medical Centers, Durham, North Carolina 27705.
Cell Metab. 2005 Sep;2(3):201-7. doi: 10.1016/j.cmet.2005.08.005.
Specific inhibitors of COX-2 have been associated with increased risk for cardiovascular complications. These agents reduce prostacyclin (PGI2) without affecting production of thromboxane (Tx) A2. While this abnormal pattern of eicosanoid generation has been implicated in the development of vascular disease associated with COX-2 inhibition, its role in the development of hypertension, the most common cardiovascular complication associated with COX-2 inhibition, is not known. We report here that mice lacking the receptor for PGI2 (IPKOs) develop salt-sensitive hypertension, cardiac hypertrophy, and severe cardiac fibrosis. Coincidental deletion of the TxA2 (TP) receptor does not prevent the development of hypertension, but cardiac hypertrophy is ameliorated and fibrosis is prevented in IPTP double knockouts (DKOs). Thus, deletion of the IP receptor removes a constraint revealing adverse cardiovascular consequences of TxA2. Our data suggest that adjuvant therapy that blocks unrestrained Tx actions might protect against end-organ damage without affecting blood pressure in patients taking COX-2 inhibitors.
COX-2特异性抑制剂与心血管并发症风险增加有关。这些药物可降低前列环素（PGI2）水平，而不影响血栓素（Tx）A2的生成。虽然这种异常的类花生酸生成模式与COX-2抑制相关的血管疾病发展有关，但其在高血压（与COX-2抑制相关的最常见心血管并发症）发展中的作用尚不清楚。我们在此报告，缺乏PGI2受体（IP基因敲除小鼠，IPKOs）的小鼠会出现盐敏感性高血压、心脏肥大和严重的心脏纤维化。同时缺失TxA2（TP）受体并不能预防高血压的发生，但在IPTP双基因敲除小鼠（DKOs）中，心脏肥大得到改善，纤维化得到预防。因此，IP受体的缺失消除了一种限制，揭示了TxA2的不良心血管后果。我们的数据表明，在服用COX-2抑制剂的患者中，阻断不受控制的Tx作用的辅助治疗可能在不影响血压的情况下预防终末器官损伤。
