Atkins Kevin B, Northcott Carrie A, Watts Stephanie W, Brosius Frank C
Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, MI 48109-0676, USA.
Am J Physiol Heart Circ Physiol. 2005 Jan;288(1):H235-43. doi: 10.1152/ajpheart.00643.2004. Epub 2004 Sep 2.
Having previously demonstrated that glucose transporter-4 (GLUT4) expression was reduced in aortas and carotid arteries of deoxycorticosterone acetate (DOCA) salt-hypertensive rats, we hypothesized that troglitazone (TG), through activation of peroxisome proliferator-activated receptor-gamma (PPAR-gamma), would stabilize GLUT4 expression and possibly preserve the differentiated phenotype in vascular smooth muscle cells. In DOCA salt-hypertensive rats treated with TG (100 mg/day), there was a significant (P < 0.001) decrease in systolic blood pressure (BP; 149.9 +/- 4.4 mmHg) compared with the untreated DOCA salt-hypertensive rats (202.2 +/- 10.34 mmHg). Separate trials with rosiglitazone (RS; 3 mg/day) demonstrated a significant (P < 0.001) decrease in BP (DOCA salt, 164.2 +/- 9.8 vs. DOCA-RS, 124.9 +/- 3.7 mmHg) comparable to that with TG. Expression of GLUT4, h-caldesmon, and smooth muscle myosin heavy chain SM2 was significantly decreased in aortas of DOCA salt-hypertensive rats and was reversed by TG to levels similar to those in aortas of sham-treated rats. TG (50 microM) induced GLUT4 and h-caldesmon expression in 24-h culture of explanted carotid arteries of DOCA salt-hypertensive rats, and the endogenous PPAR-gamma ligand 15-deoxy-Delta(12-14)-prostaglandin J(2) (PGJ(2); 20 microM) and TG (50 microM) similarly increased GLUT4, h-caldesmon, and SM2 protein expression in explanted aortas. The expression of activated, phosphorylated Akt was increased by PGJ(2) and TG with no significant effect on total Akt levels. Inhibition of phosphorylated Akt expression using the phosphatidylinositol 3-kinase inhibitor LY-294002 (16 microM) abrogated the increased expression of h-caldesmon and SM2. These data demonstrate that PPAR-gamma agonists maintain or induce expression of markers of the contractile phenotype independently of their effects on hypertension, and that this effect may be mediated through activation of phosphatidylinositol 3-kinase/Akt.
先前的研究表明，在醋酸去氧皮质酮（DOCA）盐诱导的高血压大鼠的主动脉和颈动脉中，葡萄糖转运蛋白4（GLUT4）的表达降低。我们推测，曲格列酮（TG）通过激活过氧化物酶体增殖物激活受体γ（PPAR-γ），可稳定GLUT4的表达，并可能维持血管平滑肌细胞的分化表型。在用TG（100毫克/天）治疗的DOCA盐诱导的高血压大鼠中，与未治疗的DOCA盐诱导的高血压大鼠（202.2±10.34毫米汞柱）相比，收缩压（BP）显著降低（P<0.001；149.9±4.4毫米汞柱）。罗格列酮（RS；3毫克/天）的单独试验表明，其血压显著降低（P<0.001；DOCA盐组为164.2±9.8，DOCA-RS组为124.9±3.7毫米汞柱），与TG相当。在DOCA盐诱导的高血压大鼠的主动脉中，GLUT4、h-钙调蛋白和平滑肌肌球蛋白重链SM2的表达显著降低，而TG可将其逆转至与假手术组大鼠主动脉中的水平相似。TG（50微摩尔）在DOCA盐诱导的高血压大鼠离体颈动脉24小时培养中诱导GLUT4和h-钙调蛋白的表达，内源性PPAR-γ配体15-脱氧-Δ（12-14）-前列腺素J2（PGJ2；20微摩尔）和TG（50微摩尔）同样增加了离体主动脉中GLUT4、h-钙调蛋白和SM2蛋白的表达。PGJ2和TG增加了活化的磷酸化Akt的表达，而对总Akt水平无显著影响。使用磷脂酰肌醇3激酶抑制剂LY-294002（16微摩尔）抑制磷酸化Akt的表达可消除h-钙调蛋白和SM2表达的增加。这些数据表明，PPAR-γ激动剂可独立于其对高血压的影响维持或诱导收缩表型标志物的表达，且这种作用可能通过磷脂酰肌醇3激酶/Akt的激活介导。
