Beijing Anzhen Hospital Affiliated to the Capital Medical University, The Key Laboratory of Remodeling-related Cardiovascular Diseases, Capital Medical University, Ministry of Education, Beijing Institute of Heart Lung and Blood Vessel Diseases, Beijing, China.
Cardiovasc Toxicol. 2011 Jun;11(2):157-67. doi: 10.1007/s12012-011-9109-z.
The activated renin-angiotensin-aldosterone system increases blood pressure and intracellular signals, thus leading to cardiac fibrosis. Whether increased blood pressure or angiotensin II-activated signaling is responsible for elevated angiotensin II-induced cardiac remodeling is unknown. Here, we aimed to determine whether lowering blood pressure with hydralazine might prevent inflammation and cardiac fibrosis in response to angiotensin II. We used the C57/BL6 mouse model of angiotensin II infusion (1,500 ng/kg per minute) for 7 days; 40 male mice (6 weeks old) were randomly assigned to 4 groups for treatment: mice with angiotensin II or vehicle infusion were given hydralazine in drinking water (250 mg/l per day). Heart sections were stained with hematoxylin and eosin and Masson trichrome and examined by immunohistostaining. The levels of proinflammatory cytokines were measured by real-time PCR and western blot analysis. The blood pressure of the control group began to increase on day 4 of angiotensin II infusion, and hydralazine treatment prevented angiotensin II-induced hypertension. Compared with the control, hydralazine treatment to lower blood pressure blocked angiotensin II-induced fibrosis and reduced Mac-2(+) inflammatory cell infiltration and proinflammatory cytokine expression. The accumulation of blood-borne CD45(+) cells and α-smooth muscle actin-positive myofibroblasts was also significantly reduced. Our results indicate that elevated blood pressure is essential for inflammatory cell infiltration and myofibroblast formation, which contribute to angiotensin II infusion-induced cardiac fibrosis. Hydralazine treatment attenuates cardiac fibrosis in response to angiotensin II. Lowering pressure could be an effective therapeutic target for cardiac fibrosis.
血管紧张素原-血管紧张素-醛固酮系统的激活会增加血压和细胞内信号，从而导致心脏纤维化。目前尚不清楚是血压升高还是血管紧张素 II 激活的信号导致了血管紧张素 II 诱导的心脏重构增加。在这里，我们旨在确定通过肼屈嗪降低血压是否可以预防血管紧张素 II 引起的炎症和心脏纤维化。我们使用血管紧张素 II 输注（1,500ng/kg/min）的 C57/BL6 小鼠模型 7 天；40 只雄性小鼠（6 周龄）被随机分为 4 组进行治疗：血管紧张素 II 或载体输注的小鼠给予含肼屈嗪的饮用水（每天 250mg/l）。用苏木精和伊红以及 Masson 三色染色法对心脏切片进行染色，并通过免疫组织化学染色进行检查。通过实时 PCR 和 Western blot 分析测量促炎细胞因子的水平。对照组的血压在血管紧张素 II 输注的第 4 天开始升高，肼屈嗪治疗可预防血管紧张素 II 引起的高血压。与对照组相比，肼屈嗪降压治疗可阻断血管紧张素 II 诱导的纤维化，并减少 Mac-2(+)炎性细胞浸润和促炎细胞因子表达。血液来源的 CD45(+)细胞和 α-平滑肌肌动蛋白阳性肌成纤维细胞的积累也明显减少。我们的结果表明，血压升高对于炎性细胞浸润和肌成纤维细胞形成是必需的，这有助于血管紧张素 II 输注引起的心脏纤维化。肼屈嗪治疗可减轻血管紧张素 II 引起的心脏纤维化。降低血压可能是心脏纤维化的有效治疗靶点。
