Protective Role for Tissue Inhibitor of Metalloproteinase-4, a Novel Peroxisome Proliferator–Activated Receptor-&ggr; Target Gene, in Smooth Muscle in Deoxycorticosterone Acetate–Salt Hypertension
Protective Role for Tissue Inhibitor of Metalloproteinase-4, a Novel Peroxisome Proliferator–Activated Receptor-&ggr; Target Gene, in Smooth Muscle in Deoxycorticosterone Acetate–Salt Hypertension
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金属蛋白酶-4（一种新型过氧化物酶体增殖物激活受体靶基因）组织抑制剂对脱氧皮质酮-醋酸盐高血压平滑肌的保护作用
作者：
Pimonrat Ketsawatsomkron;H. Keen;D. Davis;Ko‐ting Lu;M. Stump;T. D. De Silva;Aline M. Hilzendeger;J. Grobe;F. Faraci;C. Sigmund
过氧化物酶体增殖物激活受体（过氧化物酶体增殖物激活受体）功能的丧失会导致高血压，而其激活会降低血压。有证据表明，这些影响可能归因于血管系统中的PPAR活性。然而，在血管中的特定的转录靶点的过氧化物酶体增殖物激活受体仍然在很大程度上不明。在这项研究中，我们研究了平滑肌过氧化物酶体增殖物激活受体在盐敏感性高血压中的作用，并研究了其转录靶点和功能效应。与非转基因对照组相比，在平滑肌细胞中表达显性阴性PPAR（S-P467 L）的转基因小鼠更容易发生醋酸脱氧皮质酮盐诱导的高血压和肠系膜动脉功能障碍。尽管在基线时形态学相似，但脱氧皮质酮醋酸盐治疗后，S-P467 L中导管和小动脉的血管重塑增强。主动脉和肠系膜动脉的基因表达谱显示S-P467 L中金属蛋白酶组织抑制剂-4（TIMP-4）的表达显著降低。TIMP-4的表达增加脱氧皮质酮醋酸盐处理，但这种增加在S-P467 L消融。通过用PPAR抑制剂GW 9662处理或通过表达P467 L PPAR干扰PPAR活性显著抑制原代平滑肌细胞中的TIMP-4。在平滑肌细胞中，PPAR与染色质中靠近TIMP-4基因的PPAR反应元件（PPRE）结合，表明TIMP-4是PPAR的新靶点。干扰PPAR和TIMP-4的减少伴随着总基质金属蛋白酶活性的增加。在划痕试验中，PPAR介导的TIMP-4丢失增加，而TIMP-4过表达减少平滑肌细胞迁移。我们的研究结果强调了去氧皮质酮醋酸盐治疗中PPAR诱导的保护机制，建立了PPAR和TIMP-4之间的新型机制联系。
Loss of peroxisome proliferator–activated receptor-&ggr; (PPAR&ggr;) function causes hypertension, whereas its activation lowers blood pressure. Evidence suggests that these effects may be attributable to PPAR&ggr; activity in the vasculature. However, the specific transcriptional targets of PPAR&ggr; in vessels remain largely unidentified. In this study, we examined the role of smooth muscle PPAR&ggr; during salt-sensitive hypertension and investigated its transcriptional targets and functional effect. Transgenic mice expressing dominant-negative PPAR&ggr; (S-P467L) in smooth muscle cells were more prone to deoxycorticosterone acetate–salt–induced hypertension and mesenteric arterial dysfunction compared with nontransgenic controls. Despite similar morphometry at baseline, vascular remodeling in conduit and small arteries was enhanced in S-P467L after deoxycorticosterone acetate–salt treatment. Gene expression profiling in aorta and mesenteric arteries revealed significantly decreased expression of tissue inhibitor of metalloproteinase-4 (TIMP-4) in S-P467L. Expression of TIMP-4 was increased by deoxycorticosterone acetate–salt treatment, but this increase was ablated in S-P467L. Interference with PPAR&ggr; activity either by treatment with a PPAR&ggr; inhibitor, GW9662, or by expressing P467L PPAR&ggr; markedly suppressed TIMP-4 in primary smooth muscle cells. PPAR&ggr; binds to a PPAR response element (PPRE) in chromatin close to the TIMP-4 gene in smooth muscle cells, suggesting that TIMP-4 is a novel target of PPAR&ggr;. The interference with PPAR&ggr; and decrease in TIMP-4 were accompanied by an increase in total matrix metalloproteinase activity. PPAR&ggr;-mediated loss of TIMP-4 increased, whereas overexpression of TIMP-4 decreased smooth muscle cell migration in a scratch assay. Our findings highlight a protective mechanism induced by PPAR&ggr; in deoxycorticosterone acetate–salt treatment, establishing a novel mechanistic link between PPAR&ggr; and TIMP-4.
影响因子：
29
作者：
Halabi, Carmen M.;Beyer, Andreas M.;Sigmund, Curt D.
通讯作者：
Sigmund, Curt D.
Cullin-3通过PPARγ和RhoA/Rho-kinase调节血管平滑肌功能和动脉血压。
影响因子：
29
作者：
Pelham CJ;Ketsawatsomkron P;Groh S;Grobe JL;de Lange WJ;Ibeawuchi SR;Keen HL;Weatherford ET;Faraci FM;Sigmund CD
通讯作者：
Sigmund CD