Muthalif Mubarack M, Karzoun Nour A, Benter Ibrahim F, Gaber Lillian, Ljuca Farid, Uddin Mohammed R, Khandekar Zinat, Estes Anne, Malik Kafait U
Department of Pharmacology and Vascular Biology, Center of Excellence, College of Medicine, The University of Tennessee, Baptist Memorial Hospital, Memphis 38163, USA.
Hypertension. 2002 Feb;39(2 Pt 2):704-9. doi: 10.1161/hy0202.103823.
We have reported that norepinephrine (NE) and angiotensin II (Ang II) increase CaM kinase II activity, which, in turn, activates cytosolic phospholipase A(2) (PLA(2)) and releases arachidonic acid. The products of arachidonic acid generated via cytochrome P-450 and lipoxygenase contribute to the development of hypertension and vascular smooth muscle cell (VSMC) hyperplasia. The purpose of this study was to investigate whether CaM kinase II contributes to VSMC proliferation elicited by NE and Ang II and to hypertension induced by Ang II. NE (1 micromol/L) and Ang II (1 micromol/L) increased proliferation of rabbit aortic VSMC as measured by increased [(3)H]-thymidine incorporation; this effect of NE and Ang II was attenuated 88 +/- 10% and 64 +/- 11% by the CaM kinase II inhibitor KN-93, respectively. Infusion of Ang II with miniosmotic pumps (350 ng/min for 6 days) in rats elevated mean arterial pressure (MABP), which was reduced by simultaneous infusion of KN-93 (578 ng/min, for 6 days) (Ang II alone: MABP =174 +/- 3 mm Hg, n=12 versus Ang II + KN-93: MABP 123 +/- 5 mm Hg, n=4, P<0.05). Administration of KN-93 as a single bolus injection (16 mg/Kg), but not its vehicle, in Ang II--infused hypertensive animals also decreased MABP from 179 +/- 9 mm Hg to 109 +/- 6 mm Hg (n=5, P<0.05). CaM kinase II activity was increased in the kidney of Ang II--infused hypertensive animals compared with normotensive controls. Treatment with KN-93 reduced CaM kinase II activity and ameliorated the intravascular injury in the kidneys of Ang II--infused hypertensive rats. Our data indicate that CaM kinase activation represents an important component of the mechanism(s) initiating VSMC proliferation and the development and maintenance of Ang II--induced hypertension in rat.
我们曾报道,去甲肾上腺素(NE)和血管紧张素II(Ang II)可增加钙调蛋白激酶II的活性,进而激活胞质型磷脂酶A2(PLA2)并释放花生四烯酸。经由细胞色素P-450和脂氧合酶生成的花生四烯酸产物,会促使高血压和血管平滑肌细胞(VSMC)增生的发展。本研究的目的是探究钙调蛋白激酶II是否会促使由NE和Ang II引发的VSMC增殖以及由Ang II诱发的高血压。NE(1微摩尔/升)和Ang II(1微摩尔/升)可使兔主动脉VSMC的增殖增加,这可通过[3H] - 胸腺嘧啶核苷掺入量的增加来衡量;NE和Ang II的这种作用分别被钙调蛋白激酶II抑制剂KN - 93减弱了88±10%和64±11%。在大鼠中用微量渗透泵输注Ang II(350纳克/分钟,持续6天)会使平均动脉压(MABP)升高,而同时输注KN - 93(578纳克/分钟,持续6天)可使其降低(单独使用Ang II:MABP = 174±3毫米汞柱,n = 12;与Ang II + KN - 93相比:MABP 123±5毫米汞柱,n = 4,P < 0.05)。在输注Ang II的高血压动物中单次推注注射KN - 93(16毫克/千克)而非其溶媒,也可使MABP从179±9毫米汞柱降至109±6毫米汞柱(n = 5,P < 0.05)。与血压正常的对照组相比,输注Ang II的高血压动物肾脏中的钙调蛋白激酶II活性增加。用KN - 93治疗可降低钙调蛋白激酶II的活性,并改善输注Ang II的高血压大鼠肾脏中的血管内损伤。我们的数据表明,钙调蛋白激酶的激活是启动VSMC增殖以及大鼠中Ang II诱发的高血压的发生和维持机制的一个重要组成部分。