title: β-Arrestin mediates the Frank-Starling mechanism of cardiac contractility.
abstract: The Frank-Starling law of the heart is a physiological phenomenon that describes an intrinsic property of heart muscle in which increased cardiac filling leads to enhanced cardiac contractility. Identified more than a century ago, the Frank-Starling relationship is currently known to involve length-dependent enhancement of cardiac myofilament Ca2+sensitivity. However, the upstream molecular events that link cellular stretch to the length-dependent myofilament Ca2+sensitivity are poorly understood. Because the angiotensin II type 1 receptor (AT1R) and the multifunctional transducer protein β-arrestin have been shown to mediate mechanosensitive cellular signaling, we tested the hypothesis that these two proteins are involved in the Frank-Starling mechanism of the heart. Using invasive hemodynamics, we found that mice lacking β-arrestin 1, β-arrestin 2, or AT1R were unable to generate a Frank-Starling force in response to changes in cardiac volume. Although wild-type mice pretreated with the conventional AT1R blocker losartan were unable to enhance cardiac contractility with volume loading, treatment with a β-arrestin-biased AT1R ligand to selectively activate β-arrestin signaling preserved the Frank-Starling relationship. Importantly, in skinned muscle fiber preparations, we found markedly impaired length-dependent myofilament Ca2+sensitivity in β-arrestin 1, β-arrestin 2, and AT1R knockout mice. Our data reveal β-arrestin 1, β-arrestin 2, and AT1R as key regulatory molecules in the Frank-Starling mechanism, which potentially can be targeted therapeutically with β-arrestin-biased AT1R ligands.
authors.affiliation: Department of Medicine, Duke University Medical Center, Durham, NC 27710.
authors.forename: Dennis M
authors.initials: DM
authors.lastname: Abraham
authors.affiliation: Department of Physiology and Biophysics, University of Illinois at Chicago, Chicago, IL 60612.
authors.forename: Robert T
authors.initials: RT
authors.lastname: Davis
authors.affiliation: Department of Physiology and Biophysics, University of Illinois at Chicago, Chicago, IL 60612.
authors.forename: Chad M
authors.initials: CM
authors.lastname: Warren
authors.affiliation: Department of Medicine, Duke University Medical Center, Durham, NC 27710.
authors.forename: Lan
authors.initials: L
authors.lastname: Mao
authors.affiliation: Department of Physiology and Biophysics, University of Illinois at Chicago, Chicago, IL 60612.|Division of Cardiology, Department of Medicine, University of Illinois at Chicago, Chicago, IL 60612.
authors.forename: Beata M
authors.initials: BM
authors.lastname: Wolska
authors.affiliation: Department of Physiology and Biophysics, University of Illinois at Chicago, Chicago, IL 60612.
authors.forename: R John
authors.initials: RJ
authors.lastname: Solaro
authors.affiliation: Department of Medicine, Duke University Medical Center, Durham, NC 27710; h.rockman@duke.edu.|Department of Cell Biology, Duke University Medical Center, Durham, NC 27710.|Department of Molecular Genetics, Duke University Medical Center, Durham, NC 27710.
authors.forename: Howard A
authors.initials: HA
authors.lastname: Rockman
mesh_terms: D047228:Angiotensin II Type 1 Receptor Blockers / Q000494:pharmacology; D000818:Animals; D020013:Calcium Signaling / Q000502:physiology; D066298:In Vitro Techniques; D019808:Losartan / Q000494:pharmacology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008955:Models, Cardiovascular; D009200:Myocardial Contraction / Q000187:drug effects / Q000502:physiology*; D044140:Receptor, Angiotensin, Type 1 / Q000172:deficiency / Q000235:genetics / Q000502:physiology; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D000071559:beta-Arrestin 1 / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D000071560:beta-Arrestin 2 / Q000172:deficiency / Q000235:genetics / Q000502:physiology*
chemical_list: D047228:Angiotensin II Type 1 Receptor Blockers; C000605255:Arrb1 protein, mouse; C000605258:Arrb2 protein, mouse; D044140:Receptor, Angiotensin, Type 1; D000071559:beta-Arrestin 1; D000071560:beta-Arrestin 2; D019808:Losartan
keywords: angiotensin II type I receptor; cardiac function; hemodynamics; mechanotransduction; β-arrestin