Molecular characterization of new selective peroxisome proliferator-activated receptor γ modulators with angiotensin receptor blocking activity
Molecular characterization of new selective peroxisome proliferator-activated receptor γ modulators with angiotensin receptor blocking activity
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DOI：
10.2337/diabetes.54.12.3442
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发表时间：
2005-12-01
期刊：
影响因子：
7.7
通讯作者：
Kintscher, U
中科院分区：
文献类型：
--
作者：
Schupp, M;Clemenz, M;Kintscher, U
选择性过氧化物酶体增殖物激活受体（PPAR）γ调节是一种新的药理学方法，基于选择性受体-辅因子相互作用和靶基因调控，在不存在PPAR γ介导的不良反应的情况下，应导致有效的胰岛素增敏。在这里，我们描述了两种血管紧张素受体阻滞剂（ARB），替米沙坦和厄贝沙坦，作为新的选择性过氧化物酶体增殖物激活受体调节剂（SPPARMs）。使用蛋白酶保护对PPAR γ蛋白构象的分析表明，替米沙坦直接与受体相互作用，与格列酮相比产生了明显的构象变化。谷胱甘肽S-转移酶下拉和荧光共振能量转移试验显示，与格列酮相比，ARB选择性辅因子结合，ARB减少了核受体辅阻遏物的释放，并且不存在转录中介因子2的招募。一致地，选择性辅因子结合导致脂肪细胞（ARB与格列酮治疗）的差异基因表达谱通过寡核苷酸微阵列分析评估。最后，在没有体重增加的情况下，替米沙坦改善了饮食诱导的肥胖小鼠的胰岛素敏感性。本研究确定两种ARB为新的SPPARMs。ARB的SPPARM活性可保持PPAR γ激活的代谢功效，同时减少与AT 1受体阻断平行发挥的不良反应。这可能为代谢性疾病中更好的心血管风险管理提供新的治疗选择，并可能启动结合强效抗高血压和抗糖尿病作用的新型药物的开发。
Selective peroxisome proliferator-activated receptor (PPAR) gamma modulation is a new pharmacological approach that, based on selective receptor-cofactor interactions and target gene regulation, should result in potent insulin sensitization in the absence of PPAR gamma-mediated adverse effects. Here, we characterize two angiotensin receptor blockers (ARBs), telmisartan and irbesartan, as new selective PPAR modulators (SPPARMs). Analysis of PPAR gamma protein conformation using protease protection showed that telmisartan directly interacts with the receptor, producing a distinct conformational change compared with a glitazone. Glutathione S-transferase pull-down and fluorescence resonance energy transfer assays revealed selective cofactor binding by the ARBs compared with glitazones with an attenuated release of the nuclear receptor corepressor and absence of transcriptional intermediary factor 2 recruitment by ARBs. Consistently, selective cofactor binding resulted in differential gene expression profiles in adipocytes (ARB versus glitazone treated) assessed by oligo microarray analysis. Finally, telmisartan improved insulin sensitivity in diet-induced obese mice in the absence of weight gain. The present study identities two ARBs as new SPPARMs. SPPARM activity by ARBs could retain the metabolic efficacy of PPAR gamma activation with reduction in adverse effects exerting in parallel AT1 receptor blockade. This may provide a new therapeutic option for better cardiovascular risk management in metabolic diseases and may initiate the development of new classes of drugs combining potent antihypertensive and antidiabetic actions.