title: Integrin activation in the heart: a link between electrical and contractile dysfunction?
abstract: Integrins mechanically link the cytoskeleton to the extracellular matrix in cardiac myocytes and are thereby involved in mechanotransduction. Integrins appear to be necessary for cardiac myocyte hypertrophy. To determine the effect of increased integrin ligation and signaling on adult cardiac function, a heart-specific truncated alpha(5) integrin (gain of function) was conditionally expressed in mice. Four days later, we observed an 80% reduction in amplitude of the QRS complex, profound systolic dysfunction, decreased connexin43, loss of gap junctions, and abnormal intercalated discs. Surprisingly, isolated left ventricular myocytes contracted normally and exhibited normal Ca(2+) transients. This suggested that cell/cell electrical and/or mechanical coupling was disrupted. To distinguish electrical from mechanical coupling deficits, we compared the papillary muscle force generated by electrically stimulated versus rapid cooling contractions in which intracellular Ca(2+) is released without electrical depolarization. Both were decreased in the transgenic muscle. However, electrically stimulated contractions were more significantly reduced than rapid cooling contractures. This suggests a component of cell/cell electrical uncoupling. Optical mapping revealed a loss of the normal elliptical isochronal activation pattern implying a loss of preferential conduction through gap junctions. For the first time, we have shown that integrins can regulate both mechanical and electrical coupling in the adult heart, even in the absence of primary hemodynamic alterations. Furthermore, we demonstrated that unregulated integrin activation leads to both contractile dysfunction and arrhythmias.
authors.affiliation: Department of Biochemistry, University of Nevada School of Medicine, Reno, NV 89557, USA. mvalen@unr.edu
authors.forename: Maria L
authors.initials: ML
authors.lastname: Valencik
authors.forename: Dongfang
authors.initials: D
authors.lastname: Zhang
authors.forename: Bonnie
authors.initials: B
authors.lastname: Punske
authors.forename: Ping
authors.initials: P
authors.lastname: Hu
authors.forename: John A
authors.initials: JA
authors.lastname: McDonald
authors.forename: Sheldon E
authors.initials: SE
authors.lastname: Litwin
mesh_terms: D000818:Animals; D002118:Calcium / Q000378:metabolism; D020746:Calcium Channels, L-Type / Q000502:physiology; D037282:Calreticulin / Q000378:metabolism; D009202:Cardiomyopathies / Q000473:pathology / Q000503:physiopathology; D002450:Cell Communication / Q000502:physiology; D002463:Cell Membrane Permeability; D018031:Connexin 43 / Q000378:metabolism; D016757:Death, Sudden, Cardiac; D004562:Electrocardiography; D005355:Fibrosis; D017629:Gap Junctions / Q000502:physiology*; D006321:Heart / Q000502:physiology*; D006333:Heart Failure / Q000473:pathology / Q000503:physiopathology; D006339:Heart Rate; D039482:Integrin alpha5 / Q000235:genetics* / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D009200:Myocardial Contraction / Q000502:physiology*; D032383:Myocytes, Cardiac / Q000473:pathology / Q000502:physiology; D010210:Papillary Muscles / Q000473:pathology / Q000502:physiology; D010641:Phenotype; D015854:Up-Regulation
chemical_list: D020746:Calcium Channels, L-Type; D037282:Calreticulin; D018031:Connexin 43; D039482:Integrin alpha5; D002118:Calcium