β-adrenergic effects on cardiac myofilaments and contraction in an integrated rabbit ventricular myocyte model

Autor: Eleonora Grandi, Aldrin V. Gomes, Jose L. Puglisi, Jorge A. Negroni, Stefano Morotti, Elena C. Lascano, Donald M. Bers
Rok vydání: 2015
Předmět:
Myofilament
Contraction (grammar)
beta-adrenergic
Medical Physiology
Phospholemman
Action Potentials
Isometric exercise
Cardiorespiratory Medicine and Haematology
Cardiovascular
Myofibrils
Models
2.1 Biological and endogenous factors
Myocytes
Cardiac
Connectin
Aetiology
Myocyte model
biology
Chemistry
Models
Cardiovascular
Propranolol
Ca2+ sensitivity
Ca(2+) sensitivity
Phospholamban
Sarcoplasmic Reticulum
Titin
Rabbits
Sodium-Potassium-Exchanging ATPase
Cardiology and Cardiovascular Medicine
Cardiac
Signal Transduction
medicine.medical_specialty
Heart Ventricles
Article
Sarcoplasmic Reticulum Calcium-Transporting ATPases
Contractile model
Contractility
Adrenergic Agents
Internal medicine
medicine
Animals
Computer Simulation
Molecular Biology
Ion channel
Myocytes
Calcium-Binding Proteins
Isoproterenol
Myocardial Contraction
Cross-bridge cycling
Endocrinology
Gene Expression Regulation
Cardiovascular System & Hematology
Biophysics
biology.protein
Calcium
Software
β-adrenergic
Zdroj: Negroni, JA; Morotti, S; Lascano, EC; Gomes, AV; Grandi, E; Puglisi, JL; et al.(2015). β-adrenergic effects on cardiac myofilaments and contraction in an integrated rabbit ventricular myocyte model. Journal of Molecular and Cellular Cardiology, 81, 162-175. doi: 10.1016/j.yjmcc.2015.02.014. UC Davis: Retrieved from: http://www.escholarship.org/uc/item/0g82v46v
ISSN: 0022-2828
DOI: 10.1016/j.yjmcc.2015.02.014
Popis: A five-state model of myofilament contraction was integrated into a well-established rabbit ventricular myocyte model of ion channels, Ca(2+) transporters and kinase signaling to analyze the relative contribution of different phosphorylation targets to the overall mechanical response driven by β-adrenergic stimulation (β-AS). β-AS effect on sarcoplasmic reticulum Ca(2+) handling, Ca(2+), K(+) and Cl(-) currents, and Na(+)/K(+)-ATPase properties was included based on experimental data. The inotropic effect on the myofilaments was represented as reduced myofilament Ca(2+) sensitivity (XBCa) and titin stiffness, and increased cross-bridge (XB) cycling rate (XBcy). Assuming independent roles of XBCa and XBcy, the model reproduced experimental β-AS responses on action potentials and Ca(2+) transient amplitude and kinetics. It also replicated the behavior of force-Ca(2+), release-restretch, length-step, stiffness-frequency and force-velocity relationships, and increased force and shortening in isometric and isotonic twitch contractions. The β-AS effect was then switched off from individual targets to analyze their relative impact on contractility. Preventing β-AS effects on L-type Ca(2+) channels or phospholamban limited Ca(2+) transients and contractile responses in parallel, while blocking phospholemman and K(+) channel (IKs) effects enhanced Ca(2+) and inotropy. Removal of β-AS effects from XBCa enhanced contractile force while decreasing peak Ca(2+) (due to greater Ca(2+) buffering), but had less effect on shortening. Conversely, preventing β-AS effects on XBcy preserved Ca(2+) transient effects, but blunted inotropy (both isometric force and especially shortening). Removal of titin effects had little impact on contraction. Finally, exclusion of β-AS from XBCa and XBcy while preserving effects on other targets resulted in preserved peak isometric force response (with slower kinetics) but nearly abolished enhanced shortening. β-AS effects on XBCa and XBcy have greater impact on isometric and isotonic contraction, respectively.
Databáze: OpenAIRE
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