Troglitazone stimulates beta-arrestin-dependent cardiomyocyte contractility via the angiotensin II type 1A receptor.
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.
Tilley
Douglas G
DG
Department of Pharmaceutical Sciences, Jefferson School of Pharmacy, Thomas Jefferson University, Philadelphia, PA 19107, USA. douglas.tilley@jefferson.edu
Nguyen
Anny D
AD
Rockman
Howard A
HA
D019390:Arrestins / Q000378:metabolism*; D002460:Cell Line; D002839:Chromans / Q000494:pharmacology*; D043802:GTP-Binding Protein alpha Subunits, Gq-G11 / Q000378:metabolism; D006801:Humans; D009200:Myocardial Contraction / Q000187:drug effects*; D032383:Myocytes, Cardiac / Q000187:drug effects* / Q000378:metabolism; D047495:PPAR gamma / Q000819:agonists*; D044140:Receptor, Angiotensin, Type 1 / Q000378:metabolism*; D045162:Thiazolidinediones / Q000494:pharmacology*; D000077288:Troglitazone; D000071559:beta-Arrestin 1; D000071560:beta-Arrestin 2; D000071557:beta-Arrestins
C000605253:ARRB1 protein, human; C000605254:ARRB2 protein, human; C000605255:Arrb1 protein, mouse; C000605258:Arrb2 protein, mouse; D019390:Arrestins; D002839:Chromans; D047495:PPAR gamma; D044140:Receptor, Angiotensin, Type 1; D045162:Thiazolidinediones; D000071559:beta-Arrestin 1; D000071560:beta-Arrestin 2; D000071557:beta-Arrestins; D043802:GTP-Binding Protein alpha Subunits, Gq-G11; D000077288:Troglitazone
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