Overexpression of Gi-proteins precedes the development of DOCA-salt-induced hypertension: relationship with adenylyl cyclase
Overexpression of Gi-proteins precedes the development of DOCA-salt-induced hypertension: relationship with adenylyl cyclase
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DOI：
10.1016/s0008-6363(98)00111-4
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发表时间：
1998-08-01
影响因子：
10.8
通讯作者：
Anand-Srivastava, MB
中科院分区：
文献类型：
--
作者：
Marcil, J;de Champlain, J;Anand-Srivastava, MB
目的：在目前的研究中，我们已经调查了主动脉，如醋酸脱氧皮质酮（DOCA）-盐高血压大鼠的心脏，（HR）也表现出增强的G-蛋白水平的表达，如果这些变化发生在血压的发展之前或之后。方法：将用DOCA-盐或载体处理1、2、3和4周的Sprague-Dawley大鼠用于这些研究。通过免疫印迹法测定抑制性鸟嘌呤核苷酸调节蛋白（Gi α-2，Gi α-3）和G β蛋白的水平，而通过Northern-blotting技术测定Gi α-2和Gi α-3以及腺苷酸环化酶V型酶mRNA的水平。结果如下：与假手术大鼠相比，DOCA盐处理大鼠在处理2至4周后血压显著升高;而在处理1周后未观察到血压变化（高血压前期状态）。然而，治疗1周后，DOCA-盐治疗大鼠的心脏和主动脉中Gi α-2、Gi α-3和G β蛋白以及Gi α-2和Gi α-3 mRNA的水平显著增强，并保持升高直至治疗4周。此外，与假手术大鼠相比，在1周和更长时间的治疗（2至4周）后，血管紧张素II（Ang II）和C-ANF（4-23）对腺苷酸环化酶的Gi介导的抑制作用在DOCA-盐治疗大鼠中也更大。另一方面，Gs α的水平在DOCA-盐处理2周内没有改变，但在处理3周和4周的大鼠中显著降低。此外，与假手术大鼠相比，在DOCA盐处理1至4周后，鸟嘌呤5 '-[γ-硫代]三磷酸（GTP γ S）、异丙肾上腺素和毛喉素对心脏和主动脉腺苷酸环化酶的刺激作用均降低。腺苷酸环化酶的mRNA水平，V型酶从DOCA-盐处理大鼠心脏后3和4周的DDCA-盐处理，但不处理1或2周的大鼠显着降低。结论：这些结果表明，在DOCA盐诱导的高血压中，Gi α-2和Gi α-3的表达增强先于血压的发展。因此，可以表明Gi蛋白水平的增加和导致的cAMP水平的降低可能是导致DOCA-盐高血压中心脏收缩力受损和血管张力增加的因素之一。(C)1998 Elsevier Science B. V.保留所有权利。
Objective: In the present studies, we have investigated if aorta, like heart from deoxycorticosterone acetate (DOCA)-salt hypertensive rats, (HR) also exhibit enhanced expression of G-protein levels and if these alterations occur before or after the development of blood pressure. Methods: Sprague-Dawley rats treated with DOCA-salt or vehicle for 1, 2, 3 and 4 weeks were used for these studies. The levels of inhibitory guanine nucleotide regulatory proteins (Gi alpha-2, Gi alpha-3) and G beta proteins were determined by immunoblotting, whereas the levels of Gi alpha-2 and Gi alpha-3 and adenylyl cyclase type V enzyme mRNA were determined by Northern-blotting techniques. Results: The blood pressure was significantly increased in DOCA-salt-treated rats as compared to sham-operated rats after 2 to 4 weeks of treatment; whereas no change in blood pressure was observed after 1 week of treatment (prehypertensive state). However, the levels of Gi alpha-2, Gi alpha-3 and G beta proteins and Gi alpha-2 and Gi alpha-3 mRNA were significantly enhanced in hearts and aorta from DOCA-salt treated rats after 1 week of treatment and remained elevated up to 4 weeks of treatment. In addition, the Gi-mediated inhibitions of adenylyl cyclase by Angiotensin II (Ang II) and C-ANF(4-23) were also greater in DOCA-salt-treated rats as compared to sham-operated rats after 1 week and longer periods of treatments (2 to 4 weeks). On the other hand, the levels of Gs alpha were not altered up to 2 weeks of DOCA-salt treatment but significantly decreased in rats treated for 3 and 4 weeks. Furthermore, the stimulatory effects of guanine 5'-[gamma-thio]triphosphate (GTP gamma S), isoproterenol and forskolin on adenylyl cyclase were decreased in both hearts and aorta from DOCA-salt-treated rats after 1 to 4 weeks of treatment as compared to sham-operated rats. The mRNA levels of adenylyl cyclase, type V enzyme in hearts from DOCA-salt treated rats were significantly decreased after 3 and 4 weeks of DDCA-salt treatment but not in rats treated for 1 or 2 weeks. Conclusions: These results indicate that the enhanced expression of Gi alpha-2 and Gi alpha-3 precedes the development of blood pressure in DOCA-salt-induced hypertension. It can thus be suggested that the increased levels of Gi proteins and resulting decreased levels of cAMP may be one of the factors that contribute to the impaired cardiac contractility and increased vascular tone in DOCA-salt hypertension. (C) 1998 Elsevier Science B.V. All rights reserved.