β-Arrestin-biased AT1R stimulation promotes cell survival during acute cardiac injury.

Abstract

Pharmacological blockade of the ANG II type 1 receptor (AT1R) is a common therapy for treatment of congestive heart failure and hypertension. Increasing evidence suggests that selective engagement of β-arrestin-mediated AT1R signaling, referred to as biased signaling, promotes cardioprotective signaling. Here, we tested the hypothesis that a β-arrestin-biased AT1R ligand TRV120023 would confer cardioprotection in response to acute cardiac injury compared with the traditional AT1R blocker (ARB), losartan. TRV120023 promotes cardiac contractility, assessed by pressure-volume loop analyses, while blocking the effects of endogenous ANG II. Compared with losartan, TRV120023 significantly activates MAPK and Akt signaling pathways. These hemodynamic and biochemical effects were lost in β-arrestin-2 knockout (KO) mice. In response to cardiac injury induced by ischemia reperfusion injury or mechanical stretch, pretreatment with TRV120023 significantly diminishes cell death compared with losartan, which did not appear to be cardioprotective. This cytoprotective effect was lost in β-arrestin-2 KO mice. The β-arrestin-biased AT1R ligand, TRV120023, has cardioprotective and functional properties in vivo, which are distinct from losartan. Our data suggest that this novel class of drugs may provide an advantage over conventional ARBs by supporting cardiac function and reducing cellular injury during acute cardiac injury.

• Authors: Ki-Seok Kim, Dennis Abraham, Barbara Williams, Jonathan D Violin, Lan Mao, Howard A Rockman
• Journal: American journal of physiology. Heart and circulatory physiology (Am J Physiol Heart Circ Physiol) Vol. 303 Issue 8 Pg. H1001-10 (Oct 15 2012) ISSN: 1522-1539 [Electronic] United States
• PMID: 22886417 (Publication Type: Comparative Study, Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• Adaptor Proteins, Signal Transducing
• Agtrap protein, mouse
• Angiotensin II Type 1 Receptor Blockers
• Arrb2 protein, mouse
• Arrestins
• Cardiotonic Agents
• Oligopeptides
• beta-Arrestin 2
• beta-Arrestins
• sarcosine-arginyl-valyl-tyrosyl-lysyl-histidyl-prolyl-alanine
• Losartan

Topics

• Acute Coronary Syndrome (drug therapy, metabolism, pathology)
• Acute Disease
• Adaptor Proteins, Signal Transducing (antagonists & inhibitors, metabolism)
• Angiotensin II Type 1 Receptor Blockers (pharmacology)
• Animals
• Apoptosis (drug effects, physiology)
• Arrestins (genetics, metabolism)
• Cardiotonic Agents (pharmacology)
• Cell Survival (drug effects, physiology)
• Disease Models, Animal
• Losartan (pharmacology)
• Mice
• Mice, Inbred C57BL
• Mice, Knockout
• Myocardial Contraction (drug effects, physiology)
• Myocardium (metabolism, pathology)
• Oligopeptides (pharmacology)
• Signal Transduction (drug effects, physiology)
• beta-Arrestin 2
• beta-Arrestins