The β-arrestin-biased ligand TRV120023 inhibits angiotensin II-induced cardiac hypertrophy while preserving enhanced myofilament response to calcium

Abstract

Monasky MM, Taglieri DM, Henze M, Warren CM, Utter MS, Soergel DG, Violin JD, Solaro RJ. The ␤-arrestin-biased ligand TRV120023 inhibits angiotensin II-induced cardiac hypertrophy while preserving enhanced myofilament response to calcium. In the present study, we compared the cardioprotective effects of TRV120023, a novel angiotensin II (ANG II) type 1 receptor (AT1R) ligand, which blocks G protein coupling but stimulates ␤-arrestin signaling, against treatment with losartan, a conventional AT1R blocker in the treatment of cardiac hypertrophy and regulation of myofilament activity and phosphorylation. Rats were subjected to 3 wk of treatment with saline, ANG II, ANG II ϩ losartan, ANG II ϩ TRV120023, or TRV120023 alone. ANG II induced increased left ventricular mass compared with rats that received ANG II ϩ losartan or ANG II ϩ TRV120023. Compared with saline controls, ANG II induced a significant increase in pCa50 and maximum Ca 2ϩ -activated myofilament tension but reduced the Hill coefficient (nH). TRV120023 increased maximum tension and pCa50, although to lesser extent than ANG II. In contrast to ANG II, TRV120023 increased nH. Losartan blocked the effects of ANG II on pCa 50 and nH and reduced maximum tension below that of saline controls. ANG II ϩ TRV120023 showed responses similar to those of TRV120023 alone; compared with ANG II ϩ losartan, ANG II ϩ TRV120023 preserved maximum tension and increased both pCa 50 and cooperativity. Tropomyosin phosphorylation was lower in myofilaments from saline-treated hearts compared with the other groups. Phosphorylation of cardiac troponin I was significantly reduced in ANG II ϩ TRV120023 and TRV120023 groups versus saline controls, and myosin-binding protein C phosphorylation at Ser 282 was unaffected by ANG II or losartan but significantly reduced with TRV120023 treatment compared with all other groups. Our data indicate that TRV120023-related promotion of ␤-arrestin signaling and enhanced contractility involves a mechanism promoting the myofilament response to Ca 2ϩ via altered protein phosphorylation. Selective activation of ␤-arrestin-dependent pathways may provide advantages over conventional AT 1R blockers.␤-arrestin; hypertrophy; angiotensin; myofilament calcium sensitivity; angiotensin II type 1 receptor THERAPIES that act through the pharmacological inhibition of the renin-angiotensin-aldosterone system are routinely and effectively used, often as the first line of treatment of hypertension, chronic heart failure, cardiac remodeling after myocardial infarction, and diabetic nephropathy (6, 16). Three groups of pharmaceuticals, angiotensin-converting enzyme inhibitors, angiotensin II (ANG II) type 1 receptor (AT 1 R) blockers (ARBs), and mineralcorticoid antagonists, have been used for the past 35 yr to attenuate or reverse hypertension-induced myocardial hypertrophy and to reduce morbidity and mortality of cardiovascular disease (25, 37a, 37b).Activation of the AT 1 R, a G protein-coupled receptor, plays a pivotal role in the regulation of cardiovascular physi...

Divergent Transducer-specific Molecular Efficacies Generate Biased Agonism at a G Protein-coupled Receptor (GPCR)

“…Indeed, biased ligands at several receptors, which were first characterized in biochemical assays, have shown the cellular and in vivo pharmacology predicted from earlier studies of the underlying G protein and ␤arr pathways (57,62). Here we provide direct support for this by showing that the ␤arr2-biased molecular efficacy of TRV120023 correlates with both its extreme ␤arr2 bias in cells (17,18) and ␤arr2-mediated enhancement of cardiac performance in vivo (18,20,21). Moreover, the closely related peptide TRV120027, which exhibits a similar efficacy profile, is now in clinical trials for the treatment of acute heart failure (63).…”

β-Arrestin mediates the Frank–Starling mechanism of cardiac contractility

“…Measurements of the force-Ca 2+ relationship were performed in detergent-extracted fiber bundles isolated from papillary muscles of WT (10 fibers, 10 mice), β-arrestin 2 KO (11 fibers, 11 mice), β-arrestin 1 KO (10 fibers, 10 mice), and AT1R (13 fibers, 13 mice) mice as described previously (46). Adult male mice were anesthetized by i.p.…”

The G Protein–Biased κ-Opioid Receptor Agonist RB-64 Is Analgesic with a Unique Spectrum of Activities In Vivo

“…Currently, the potential of functionally selective drugs as biased agonists for a wide range of targets and disease states is being investigated. Thus, for instance, 1) angiotensin II receptor arrestin-biased agonists are being investigated for treating acute heart failure; 2) m-opioid receptor G protein biased agonists have been proposed as novel analgesics; 3) d-opioid receptor G protein-biased agonists are being considered for Parkinson disease, pain, and depression; and 4) the dopamine D 2 arrestin-biased agonists are being evaluated for treating schizophrenia and related disorders Pradhan et al, 2011;Whalen et al, 2011;DeWire et al, 2013;Monasky et al, 2013). Significantly, a wealth of data implies that G protein-biased KOR ligands might represent novel analgesics with lower addiction liability and fewer side effects (Bruchas et al, 2007;Tao et al, 2008;Ranganathan et al, 2012).…”