title: Caveolae in ventricular myocytes are required for stretch-dependent conduction slowing.
abstract: Mechanical stretch of cardiac muscle modulates action potential propagation velocity, causing potentially arrhythmogenic conduction slowing. The mechanisms by which stretch alters cardiac conduction remain unknown, but previous studies suggest that stretch can affect the conformation of caveolae in myocytes and other cell types. We tested the hypothesis that slowing of action potential conduction due to cardiac myocyte stretch is dependent on caveolae. Cardiac action potential propagation velocities, measured by optical mapping in isolated mouse hearts and in micropatterned mouse cardiomyocyte cultures, decreased reversibly with volume loading or stretch, respectively (by 19±5% and 26±4%). Stretch-dependent conduction slowing was not altered by stretch-activated channel blockade with gadolinium or by GsMTx-4 peptide, but was inhibited when caveolae were disrupted via genetic deletion of caveolin-3 (Cav3 KO) or membrane cholesterol depletion by methyl-β-cyclodextrin. In wild-type mouse hearts, stretch coincided with recruitment of caveolae to the sarcolemma, as observed by electron microscopy. In myocytes from wild-type but not Cav3 KO mice, stretch significantly increased cell membrane capacitance (by 98±64%), electrical time constant (by 285±149%), and lipid recruitment to the bilayer (by 84±39%). Recruitment of caveolae to the sarcolemma during physiologic cardiomyocyte stretch slows ventricular action potential propagation by increasing cell membrane capacitance.
authors.affiliation: Department of Bioengineering, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA 92093-0412, USA.
authors.forename: E R
authors.initials: ER
authors.lastname: Pfeiffer
authors.affiliation: Department of Bioengineering, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA 92093-0412, USA.
authors.forename: A T
authors.initials: AT
authors.lastname: Wright
authors.affiliation: Department of Bioengineering, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA 92093-0412, USA.
authors.forename: A G
authors.initials: AG
authors.lastname: Edwards
authors.affiliation: Department of Bioengineering, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA 92093-0412, USA.
authors.forename: J C
authors.initials: JC
authors.lastname: Stowe
authors.affiliation: Department of Bioengineering, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA 92093-0412, USA.
authors.forename: K
authors.initials: K
authors.lastname: McNall
authors.affiliation: Department of Bioengineering, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA 92093-0412, USA.
authors.forename: J
authors.initials: J
authors.lastname: Tan
authors.affiliation: Department of Anesthesiology, VA San Diego Healthcare System, and University of California, San Diego, 9500 Gilman Drive, La Jolla, CA 92093-9125, USA.
authors.forename: I
authors.initials: I
authors.lastname: Niesman
authors.affiliation: Department of Anesthesiology, VA San Diego Healthcare System, and University of California, San Diego, 9500 Gilman Drive, La Jolla, CA 92093-9125, USA.
authors.forename: H H
authors.initials: HH
authors.lastname: Patel
authors.affiliation: Department of Anesthesiology, VA San Diego Healthcare System, and University of California, San Diego, 9500 Gilman Drive, La Jolla, CA 92093-9125, USA.
authors.forename: D M
authors.initials: DM
authors.lastname: Roth
authors.affiliation: Department of Bioengineering, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA 92093-0412, USA; Department of Medicine, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA 92093-0613, USA.
authors.forename: J H
authors.initials: JH
authors.lastname: Omens
authors.affiliation: Department of Bioengineering, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA 92093-0412, USA; Department of Medicine, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA 92093-0613, USA. Electronic address: amcculloch@ucsd.edu.
authors.forename: A D
authors.initials: AD
authors.lastname: McCulloch
mesh_terms: D000200:Action Potentials; D000818:Animals; D021941:Caveolae / Q000502:physiology*; D051244:Caveolin 3 / Q000235:genetics / Q000378:metabolism; D002478:Cells, Cultured; D006329:Heart Conduction System; D006352:Heart Ventricles / Q000166:cytology; D040542:Mechanotransduction, Cellular; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D032383:Myocytes, Cardiac / Q000502:physiology* / Q000648:ultrastructure; D018408:Patch-Clamp Techniques; D012508:Sarcolemma / Q000378:metabolism; D016276:Ventricular Function; D017725:Ventricular Pressure
chemical_list: C495548:Cav3 protein, mouse; D051244:Caveolin 3
keywords: Capacitance; Cardiac mechanoelectric feedback; Caveolae