Department of Pharmaceutical Sciences, Jefferson School of Pharmacy, Thomas Jefferson University, Philadelphia, PA 19107, USA.
Biochem Biophys Res Commun. 2010 Jun 11;396(4):921-6. doi: 10.1016/j.bbrc.2010.05.023. Epub 2010 May 10.
Peroxisome proliferator-activated receptor gamma (PPAR gamma) agonists are commonly used to treat cardiovascular diseases, and are reported to have several effects on cardiovascular function that may be due to PPAR gamma-independent signaling events. Select angiotensin receptor blockers (ARBs) interact with and modulate PPAR gamma activity, thus we hypothesized that a PPAR gamma agonist may exert physiologic effects via the angiotensin II type 1(A) receptor (AT1(A)R). In AT1(A)R-overexpressing HEK 293 cells, both angiotensin II (Ang II) and the PPAR gamma agonist troglitazone (Trog) enhanced AT1(A)R internalization and recruitment of endogenous beta-arrestin 1/2 (beta arr1/2) to the AT1(A)R. A fluorescence assay to measure diacylglycerol (DAG) accumulation showed that although Ang II induced AT1(A)R-G(q) protein-mediated DAG accumulation, Trog had no impact on DAG generation. Trog-mediated recruitment of beta arr1/2 was selective to AT1(A)R as the response was prevented by an ARB- and Trog-mediated beta arr1/2 recruitment to beta1-adrenergic receptor (beta 1AR) was not observed. In isolated mouse cardiomyocytes, Trog increased both % and rate of cell shortening to a similar extent as Ang II, effects which were blocked with an ARB. Additionally, these effects were found to be beta arr2-dependent, as cardiomyocytes isolated from beta arr2-KO mice showed blunted contractile responses to Trog. These findings show for the first time that the PPAR gamma agonist Trog acts at the AT1(A)R to simultaneously block G(q) protein activation and induce the recruitment of beta arr1/2, which leads to an increase in cardiomyocyte contractility.
过氧化物酶体增殖物激活受体γ（PPARγ）激动剂常用于治疗心血管疾病，据报道，其对心血管功能有多种影响，这可能是由于 PPARγ 非依赖性信号事件所致。某些血管紧张素受体阻滞剂（ARB）与 PPARγ 相互作用并调节其活性，因此我们假设 PPARγ 激动剂可能通过血管紧张素 II 型 1（A）受体（AT1（A）R）发挥生理作用。在过表达 AT1（A）R 的 HEK 293 细胞中，血管紧张素 II（Ang II）和 PPARγ 激动剂曲格列酮（Trog）均增强 AT1（A）R 的内化以及内源性β-arrestin 1/2（β arr1/2）募集到 AT1（A）R。荧光测定法测量二酰基甘油（DAG）积累表明，尽管 Ang II 诱导 AT1（A）R-G（q）蛋白介导的 DAG 积累，但 Trog 对 DAG 的产生没有影响。Trog 介导的β arr1/2 募集是对 AT1（A）R 具有选择性的，因为 ARB 和 Trog 介导的β arr1/2 募集到β1-肾上腺素能受体（β 1AR）不会引起反应。在分离的小鼠心肌细胞中，Trog 使细胞缩短的百分比和速率均增加到与 Ang II 相似的程度，而 ARB 可阻断这种作用。此外，这些作用依赖于β arr2，因为从β arr2-KO 小鼠分离的心肌细胞对 Trog 的收缩反应减弱。这些发现首次表明，PPARγ 激动剂 Trog 通过 AT1（A）R 作用，同时阻断 G（q）蛋白的激活并诱导β arr1/2 的募集，从而导致心肌细胞收缩力增加。
