title: Galphas-biased beta2-adrenergic receptor signaling from restoring synchronous contraction in the failing heart.
abstract: Cardiac resynchronization therapy (CRT), in which both ventricles are paced to recoordinate contraction in hearts that are dyssynchronous from conduction delay, is the only heart failure (HF) therapy to date to clinically improve acute and chronic function while also lowering mortality. CRT acutely enhances chamber mechanical efficiency but chronically alters myocyte signaling, including improving β-adrenergic receptor reserve. We speculated that the latter would identify unique CRT effects that might themselves be effective for HF more generally. HF was induced in dogs by 6 weeks of atrial rapid pacing with (HFdys, left bundle ablated) or without (HFsyn) dyssynchrony. We used dyssynchronous followed by resynchronized tachypacing (each 3 weeks) for CRT. Both HFdys and HFsyn myocytes had similarly depressed rest and β-adrenergic receptor sarcomere and calcium responses, particularly the β2-adrenergic response, whereas cells subjected to CRT behaved similarly to those from healthy controls. CRT myocytes exhibited suppressed Gαi signaling linked to increased regulator of G protein (heterotrimeric guanine nucleotide-binding protein) signaling (RGS2, RGS3), yielding Gαs-biased β2-adrenergic responses. This included increased adenosine cyclic AMP responsiveness and activation of sarcoplasmic reticulum-localized protein kinase A. Human CRT responders also showed up-regulated myocardial RGS2 and RGS3. Inhibition of Gαi (with pertussis toxin, RGS3, or RGS2 transfection), stimulation with a Gαs-biased β2 agonist (fenoterol), or transient (2-week) exposure to dyssynchrony restored β-adrenergic receptor responses in HFsyn to the values obtained after CRT. These results identify a key pathway that is triggered by restoring contractile synchrony and that may represent a new therapeutic approach for a broad population of HF patients.
authors.affiliation: Division of Cardiology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
authors.forename: Khalid
authors.initials: K
authors.lastname: Chakir
authors.forename: Charlene
authors.initials: C
authors.lastname: Depry
authors.forename: Veronica L
authors.initials: VL
authors.lastname: Dimaano
authors.forename: Wei-Zhong
authors.initials: WZ
authors.lastname: Zhu
authors.forename: Marc
authors.initials: M
authors.lastname: Vanderheyden
authors.forename: Jozef
authors.initials: J
authors.lastname: Bartunek
authors.forename: Theodore P
authors.initials: TP
authors.lastname: Abraham
authors.forename: Gordon F
authors.initials: GF
authors.lastname: Tomaselli
authors.forename: Shu-bai
authors.initials: SB
authors.lastname: Liu
authors.forename: Yang K
authors.initials: YK
authors.lastname: Xiang
authors.forename: Manling
authors.initials: M
authors.lastname: Zhang
authors.forename: Eiki
authors.initials: E
authors.lastname: Takimoto
authors.forename: Nickolai
authors.initials: N
authors.lastname: Dulin
authors.forename: Rui Ping
authors.initials: RP
authors.lastname: Xiao
authors.forename: Jin
authors.initials: J
authors.lastname: Zhang
authors.forename: David A
authors.initials: DA
authors.lastname: Kass
mesh_terms: D000818:Animals; D058406:Cardiac Resynchronization Therapy; D002478:Cells, Cultured; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D004285:Dogs; D031541:Fluorescence Resonance Energy Transfer; D019204:GTP-Binding Proteins / Q000378:metabolism; D020690:GTPase-Activating Proteins / Q000378:metabolism; D006333:Heart Failure / Q000378:metabolism* / Q000628:therapy*; D020962:Heterotrimeric GTP-Binding Proteins / Q000378:metabolism; D006801:Humans; D066298:In Vitro Techniques; D032342:Muscle Cells / Q000378:metabolism; D009206:Myocardium / Q000378:metabolism; D020710:RGS Proteins / Q000378:metabolism; D018343:Receptors, Adrenergic, beta-2 / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*
chemical_list: D020690:GTPase-Activating Proteins; D020710:RGS Proteins; C087182:RGS2 protein, human; C485898:RGS3 protein, human; D018343:Receptors, Adrenergic, beta-2; D017868:Cyclic AMP-Dependent Protein Kinases; D019204:GTP-Binding Proteins; D020962:Heterotrimeric GTP-Binding Proteins