Liu Dongmei, Gao Lie, Roy Shyamal K, Cornish Kurtis G, Zucker Irving H
Department of Cellular and Integrative Physiology, University of Nebraska Medical Center, 985850 Nebraska Medical Center, Omaha, NE 68198-5850, USA.
Circ Res. 2006 Oct 27;99(9):1004-11. doi: 10.1161/01.RES.0000247066.19878.93. Epub 2006 Sep 28.
Chronic heart failure (CHF) is a leading cause of mortality in developed countries. Angiotensin II (Ang II) plays an important role in the development and progression of CHF. Many of the important functions of Ang II are mediated by the Ang II type 1 receptor (AT(1)R), including the increase in sympathetic nerve activity in CHF. However, the central regulation of the AT(1)R in the setting of CHF is not well understood. This study investigated the AT(1)R in the rostral ventrolateral medulla (RVLM) of rabbits with CHF, its downstream pathway, and its gene regulation by the transcription factor activator protein 1 (AP-1). Studies were performed in 5 groups of rabbits: sham (n=5), pacing-induced (3 to 4 weeks) CHF (n=5), CHF with intracerebroventricular (ICV) losartan treatment (n=5), normal with ICV Ang II treatment (n=5), and normal with ICV Ang II plus losartan treatment (n=5). AT(1)R mRNA and protein expressions, plasma Ang II, and AP-1-DNA binding activity were significantly higher in RVLM of CHF compared with Sham rabbits (240.4+/-30.2%, P<0.01; 206.6+/-25.8%, P<0.01; 280+/-36.5%, P<0.05; 207+/-16.4%, P<0.01, respectively). Analysis of the stress-activated protein kinase/Jun N-terminal kinase (SAPK/JNK) pathway showed that phosphorylated c-Jun proteins, phosphorylated JNK proteins, and JNK activity increased significantly in RVLM of CHF compared with sham (262.9+/-48.1%, 213.8+/-27.7%, 148.2+/-10.1% of control, respectively). Importantly, ICV losartan in CHF rabbits attenuated these increases. ICV Ang II in normal rabbits simulated the molecular changes seen in CHF. This effect was blocked by concomitant ICV losartan. In addition, Ang II-induced AT(1)R expression was blocked by losartan and a JNK inhibitor, but not by extracellular signal-regulated kinase or p38 MAP kinase inhibitors in a neuronal cell culture. These data suggest that central Ang II activates the AT(1)R, SAPK/JNK pathway. AP-1 may further regulate gene expression in RVLM in the CHF state.
慢性心力衰竭（CHF）是发达国家主要的死亡原因。血管紧张素II（Ang II）在CHF的发生和发展中起重要作用。Ang II的许多重要功能是由血管紧张素II 1型受体（AT(1)R）介导的，包括CHF中交感神经活性的增加。然而，在CHF情况下AT(1)R的中枢调节尚不清楚。本研究调查了CHF家兔延髓头端腹外侧区（RVLM）中的AT(1)R、其下游途径以及转录因子激活蛋白1（AP-1）对其基因的调控。对5组家兔进行了研究：假手术组（n = 5）、起搏诱导（3至4周）的CHF组（n = 5）、经脑室内（ICV）给予氯沙坦治疗的CHF组（n = 5）、经ICV给予Ang II治疗的正常组（n = 5）以及经ICV给予Ang II加氯沙坦治疗的正常组（n = 5）。与假手术家兔相比，CHF家兔RVLM中AT(1)R mRNA和蛋白表达、血浆Ang II以及AP-1-DNA结合活性显著更高（分别为240.4±30.2%，P<0.01；206.6±25.8%，P<0.01；280±36.5%，P<0.05；207±16.4%，P<0.01）。对应激激活蛋白激酶/应激活化蛋白激酶（SAPK/JNK）途径的分析表明，与假手术组相比，CHF家兔RVLM中磷酸化c-Jun蛋白、磷酸化JNK蛋白以及JNK活性显著增加（分别为对照组的262.9±48.1%、213.8±27.7%、148.2±10.1%）。重要的是，CHF家兔经ICV给予氯沙坦可减弱这些增加。正常家兔经ICV给予Ang II模拟了CHF中所见的分子变化。这种效应被同时给予的ICV氯沙坦阻断。此外，在神经元细胞培养中，Ang II诱导的AT(1)R表达被氯沙坦和一种JNK抑制剂阻断，但未被细胞外信号调节激酶或p38丝裂原活化蛋白激酶抑制剂阻断。这些数据表明，中枢Ang II激活AT(1)R、SAPK/JNK途径。在CHF状态下，AP-1可能进一步调节RVLM中的基因表达。
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