title: Calcium dysregulation in ventricular myocytes from mice expressing constitutively active Rac1.
abstract: Increased Rac1 activity and its concomitant elevation of reactive oxygen species (ROS) levels is believed to be involved in the development of cardiac diseases such as hypertrophy and arrhythmia. To study the effects of activated Rac1 on the properties of isolated ventricular myocytes we used a transgenic mouse model (RacET) expressing constitutively active Rac1. Concurrent with dilated cardiomyopathy global Ca(2+) handling as well as single cell contractility was substantially decreased. Cellular ROS levels were assessed with two independent assays and unexpectedly depicted decreased ROS production in RacET that was uncoupled from hormonal stimulation. Western blot analysis illustrated a massive increase in cellular Rac1 activity concomitant with a reduction in NADPH-oxidase activity. Analysis of the Ca(2+) current, the ryanodine receptor and fractional Ca(2+) release uncovered defective excitation-contraction (ec) coupling and a substantial increase in sarcoplasmic reticulum Ca(2+) leak together with a larger Ca(2+) spark amplitude and frequency. We conclude that Rac1 activity plays an important role for cardiac diseases but can be uncoupled from NADPH-oxidase activity. Rac1-mediated partial uncoupling of the ec-coupling machinery results in a ROS-independent disarrayed cellular Ca(2+) handling, contractility and impaired cardiac function.
authors: Institute for Molecular Cell Biology, Saarland University, 66421 Homburg/Saar, Germany.
authors: Martin
authors: M
authors: Oberhofer
authors: Qinghai
authors: Q
authors: Tian
authors: Sandra
authors: S
authors: Ruppenthal
authors: Silke
authors: S
authors: Wegener
authors: Jan-Christian
authors: JC
authors: Reil
authors: Christina
authors: C
authors: Körbel
authors: Karin
authors: K
authors: Hammer
authors: Michael
authors: M
authors: Menger
authors: Hans-Ruprecht
authors: HR
authors: Neuberger
authors: Lars
authors: L
authors: Kaestner
authors: Peter
authors: P
authors: Lipp
mesh_terms: D000200:Action Potentials / Q000502:physiology; D000818:Animals; D002118:Calcium / Q000378:metabolism*; D020746:Calcium Channels, L-Type / Q000502:physiology; D002478:Cells, Cultured; D006352:Heart Ventricles / Q000166:cytology*; D066298:In Vitro Techniques; D008297:Male; D008562:Membrane Glycoproteins / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D023421:Models, Animal; D032383:Myocytes, Cardiac / Q000166:cytology* / Q000378:metabolism*; D000074662:NADPH Oxidase 2; D019255:NADPH Oxidases / Q000378:metabolism; D009479:Neuropeptides / Q000235:genetics / Q000378:metabolism*; D017382:Reactive Oxygen Species / Q000378:metabolism; D012519:Sarcoplasmic Reticulum / Q000378:metabolism; D020830:rac1 GTP-Binding Protein / Q000235:genetics / Q000378:metabolism*
chemical_list: D020746:Calcium Channels, L-Type; D008562:Membrane Glycoproteins; D009479:Neuropeptides; C484602:Rac1 protein, mouse; D017382:Reactive Oxygen Species; C488842:Cybb protein, mouse; D000074662:NADPH Oxidase 2; D019255:NADPH Oxidases; D020830:rac1 GTP-Binding Protein; D002118:Calcium