Ferreira Anderson J, Shenoy Vinayak, Yamazato Yoriko, Sriramula Srinivas, Francis Joseph, Yuan Lihui, Castellano Ronald K, Ostrov David A, Oh Suk Paul, Katovich Michael J, Raizada Mohan K
Department of Physiology and Functional Genomics, College of Medicine, Gainesville, FL 32610, USA.
Am J Respir Crit Care Med. 2009 Jun 1;179(11):1048-54. doi: 10.1164/rccm.200811-1678OC. Epub 2009 Feb 26.
It has been proposed that an activated renin angiotensin system (RAS) causes an imbalance between the vasoconstrictive and vasodilator mechanisms involving the pulmonary circulation leading to the development of pulmonary hypertension (PH). Recent studies have indicated that angiotensin-converting enzyme 2 (ACE2), a member of the vasoprotective axis of the RAS, plays a regulatory role in lung pathophysiology, including pulmonary fibrosis and acute lung disease. Based on these observations, we propose the hypothesis that activation of endogenous ACE2 can shift the balance from the vasoconstrictive, proliferative axis (ACE-Ang II-AT1R) to the vasoprotective axis [ACE2-Ang-(1-7)-Mas] of the RAS, resulting in the prevention of PH.
We have taken advantage of a recently discovered synthetic activator of ACE2, XNT (1-[(2-dimethylamino) ethylamino]-4-(hydroxymethyl)-7-[(4-methylphenyl) sulfonyl oxy]-9H-xanthene-9-one), to study its effects on monocrotaline-induced PH in rats to support this hypothesis.
The cardiopulmonary effects of XNT were evaluated in monocrotaline-induced PH rat model.
A single subcutaneous treatment of monocrotaline in rats resulted in elevated right ventricular systolic pressure, right ventricular hypertrophy, increased pulmonary vessel wall thickness, and interstitial fibrosis. These changes were associated with increases in the mRNA levels of renin, ACE, angiotensinogen, AT1 receptors, and proinflammatory cytokines. All these features of PH were prevented in these monocrotaline-treated rats by chronic treatment with XNT. In addition, XNT caused an increase in the antiinflammatory cytokine, IL-10.
These observations provide conceptual support that activation of ACE2 by a small molecule can be a therapeutically relevant approach for treating and controlling PH.
有人提出，激活的肾素血管紧张素系统（RAS）会导致涉及肺循环的血管收缩和血管舒张机制失衡，从而引发肺动脉高压（PH）。最近的研究表明，血管紧张素转换酶2（ACE2）是RAS血管保护轴的成员，在肺病理生理学中发挥调节作用，包括肺纤维化和急性肺疾病。基于这些观察结果，我们提出假设，即内源性ACE2的激活可使平衡从RAS的血管收缩、增殖轴（ACE-血管紧张素II-血管紧张素II 1型受体）转向血管保护轴[ACE2-血管紧张素（1-7）-Mas]，从而预防PH。
我们利用最近发现的一种ACE2合成激活剂XNT（1-[(2-二甲基氨基)乙氨基]-4-(羟甲基)-7-[(4-甲基苯基)磺酰氧基]-9H-占吨-9-酮），研究其对大鼠野百合碱诱导的PH的影响，以支持这一假设。
在野百合碱诱导的PH大鼠模型中评估XNT的心肺效应。
大鼠单次皮下注射野百合碱导致右心室收缩压升高、右心室肥厚、肺血管壁厚度增加和间质纤维化。这些变化与肾素、ACE、血管紧张素原、血管紧张素II 1型受体和促炎细胞因子的mRNA水平升高有关。通过用XNT进行慢性治疗，这些野百合碱处理的大鼠中PH的所有这些特征均得到预防。此外，XNT导致抗炎细胞因子IL-10增加。
这些观察结果提供了概念性支持，即小分子激活ACE2可能是治疗和控制PH的一种与治疗相关的方法。
