Department of Cardiology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai 200072, P.R. China.
Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education and Chinese Ministry of Health, Qilu Hospital of Shandong University, Jinan, Shandong 250000, P.R. China.
Mol Med Rep. 2017 Aug;16(2):1360-1368. doi: 10.3892/mmr.2017.6706. Epub 2017 Jun 6.
It has previously been demonstrated that the renin-angiotensin system is involved in the pathogenesis and development of pulmonary hypertension (PH). However, the efficacy of angiotensin II type I (AT1) receptor blockers in the treatment of PH is variable. The present study examined the effects of the AT1 receptor blocker valsartan on monocrotaline (MCT)‑induced PH in rats and chronic hypoxia‑induced PH in mice. The results demonstrated that valsartan markedly attenuated development of PH in rats and mice, as indicated by reduced right ventricular systolic pressure, diminished lung vascular remodeling and decreased right ventricular hypertrophy, compared with vehicle treated animals. Immunohistochemical analyses of proliferating cell nuclear antigen expression revealed that valsartan suppressed smooth muscle cell proliferation. Western blot analysis demonstrated that valsartan limited activation of p38, c‑Jun N‑terminal kinase 1/2 and extracellular signal‑regulated kinase 1/2 signaling pathways and significantly reduced MCT‑induced upregulation of pulmonary matrix metalloproteinases‑2 and ‑9, and transforming growth factor‑β1 expression. The results suggested that valsartan attenuates development of PH in rodents by reducing expression of extracellular matrix remodeling factors and limiting smooth muscle cell proliferation to decrease pathological vascular remodeling. Therefore, valsartan may be a valuable future therapeutic approach for the treatment of PH.
先前已有研究表明，肾素-血管紧张素系统（renin-angiotensin system）参与了肺动脉高压（pulmonary hypertension，PH）的发病机制和发展过程。然而，血管紧张素 II 型 1 型（angiotensin II type 1，AT1）受体阻滞剂在 PH 治疗中的疗效存在差异。本研究探讨了 AT1 受体阻滞剂缬沙坦（valsartan）对野百合碱（monocrotaline，MCT）诱导的大鼠 PH 和慢性低氧诱导的小鼠 PH 的影响。结果表明，与对照组动物相比，缬沙坦明显减轻了大鼠和小鼠 PH 的发展，表现为右心室收缩压降低、肺血管重构减轻和右心室肥厚减轻。增殖细胞核抗原表达的免疫组织化学分析表明，缬沙坦抑制了平滑肌细胞增殖。Western blot 分析表明，缬沙坦限制了 p38、c-Jun N-末端激酶 1/2 和细胞外信号调节激酶 1/2 信号通路的激活，并显著降低了 MCT 诱导的肺基质金属蛋白酶-2 和 -9 以及转化生长因子-β1 的表达上调。结果表明，缬沙坦通过减少细胞外基质重塑因子的表达和限制平滑肌细胞增殖来减少病理性血管重构，从而减轻了啮齿动物 PH 的发展。因此，缬沙坦可能成为治疗 PH 的一种有价值的未来治疗方法。
