El Mabrouk M, Touyz R M, Schiffrin E L
Multidisciplinary Research Group on Hypertension, Clinical Research Institute of Montreal, University of Montreal, Montreal, Quebec, Canada H2W 1R7.
Am J Physiol Heart Circ Physiol. 2001 Jul;281(1):H30-9. doi: 10.1152/ajpheart.2001.281.1.H30.
Angiotensin II-induced growth signaling mechanisms were investigated in vascular smooth muscle cells (VSMCs) from mesenteric arteries of spontaneously hypertensive (SHR) and Wistar-Kyoto rats (WKY). In WKY, angiotensin II significantly increased protein synthesis ([(3)H]leucine incorporation) but not DNA synthesis ([(3)H]thymidine incorporation). In SHR, angiotensin II increased protein and DNA synthesis. VSMCs from both strains expressed angiotensin type 1 (AT(1)) and type 2 (AT(2)) receptors. Losartan (an AT(1) receptor antagonist) but not PD-123319 (an AT(2) receptor antagonist) attenuated angiotensin II-stimulated protein synthesis in WKY VSMCs. In SHR, losartan and PD-123319 partially inhibited angiotensin II-induced VSMC proliferation. The mitogen-activated protein kinase or extracellular signal-regulated protein kinase (ERK) kinase inhibitor PD-98059 blocked VSMC growth responses to angiotensin II in both strains. Angiotensin II increased ERK1/2 activation more in SHR than WKY, an effect inhibited by losartan but not PD-123319. LY-294002 [a phosphatidylinositol-3 (PI3) kinase inhibitor] blocked angiotensin II-stimulated ERK1/2 activation in SHR but not in WKY, whereas bisindolylmaleimide [a protein kinase C (PKC) inhibitor] was ineffective. In conclusion, angiotensin II stimulates VSMC proliferation via AT(1) and AT(2) receptors in SHR. In WKY, angiotensin II induces VSMC hypertrophy via AT(1) receptors. ERK1/2-dependent pathways regulated by intracellular Ca(2+) but not PKC mediate these effects. In SHR VSMCs, PI3 kinase plays a role in augmented angiotensin II-induced ERK1/2 phosphorylation. These angiotensin II-mediated signaling events could contribute to vascular remodeling in SHR.
研究了自发性高血压大鼠（SHR）和Wistar-Kyoto大鼠（WKY）肠系膜动脉血管平滑肌细胞（VSMC）中血管紧张素II诱导的生长信号机制。在WKY中，血管紧张素II显著增加蛋白质合成（[³H]亮氨酸掺入），但不增加DNA合成（[³H]胸腺嘧啶掺入）。在SHR中，血管紧张素II增加蛋白质和DNA合成。两种品系的VSMC均表达血管紧张素1型（AT₁）和2型（AT₂）受体。氯沙坦（一种AT₁受体拮抗剂）而非PD-123319（一种AT₂受体拮抗剂）减弱了WKY VSMC中血管紧张素II刺激的蛋白质合成。在SHR中，氯沙坦和PD-123319部分抑制血管紧张素II诱导的VSMC增殖。丝裂原活化蛋白激酶或细胞外信号调节蛋白激酶（ERK）激酶抑制剂PD-98059阻断了两种品系VSMC对血管紧张素II的生长反应。血管紧张素II在SHR中比在WKY中更能增加ERK1/2的活化，氯沙坦可抑制这一作用，而PD-123319则无此作用。LY-294002（一种磷脂酰肌醇-3（PI3）激酶抑制剂）阻断了SHR中血管紧张素II刺激的ERK1/2活化，但未阻断WKY中的活化，而双吲哚马来酰胺（一种蛋白激酶C（PKC）抑制剂）则无效。总之，血管紧张素II通过SHR中的AT₁和AT₂受体刺激VSMC增殖。在WKY中，血管紧张素II通过AT₁受体诱导VSMC肥大。细胞内Ca²⁺而非PKC调节的ERK1/2依赖性途径介导了这些作用。在SHR VSMC中，PI3激酶在血管紧张素II诱导的ERK1/2磷酸化增强中起作用。这些血管紧张素II介导的信号事件可能导致SHR中的血管重塑。
