Annexin vi overexpression targeted to heart alters cardiomyocyte
function in transgenic mice.
Gunteski-Hamblin, Ann-Marie, Guojie Song, Richard A. Walsh, Marie
Frenzke, Gregory P. Boivin, Gerald W. Dorn Ii, Marcia A. Kaetzel,
Nelson D. Horseman, and John R. Dedman.
Department of Molecular and Cellular Physiology, and the Department
of Internal Medicine, Division of Cardiology, and the Department of
Pathology and Laboratory Medicine, University of Cincinnati College
of Medicine, Cincinnati, Ohio 45267-0576
APStracts 2:0419H, 1995.
Annexin VI is a member of a family of Ca2+-dependent phospholipid
binding proteins that is expressed in many tissues including the
heart. It is a regulator of membrane-associated events including the
skeletal muscle ryanodine-sensitive Ca2+ release channel and the
cardiac Na+/Ca2+ exchanger. The potential roles of annexin VI in Ca2+
signaling in cardiac myocytes was evaluated by targeting its
overexpression to the hearts of transgenic mice. Expression of full
-length human annexin VI cDNA was targeted to heart using the alpha
myosin heavy chain gene promoter (Subramaniam, et al., J. Biol. Chem.
266:24613-24620). Five transgenic lines exhibited at least 10-fold
overexpression of annexin VI protein in both atria and ventricles.
Pathological evaluation indicated mice overexpressing annexin VI had
enlarged, dilated hearts, acute diffuse myocarditis, lymphocytic
infiltration and moderate to severe fibrosis throughout the heart,
and mild fibrosis around the pulmonary veins of the lungs.
Contractile mechanics of cardiomyocytes isolated from hearts of
transgenic animals showed frequency dependent reduced percent
shortening, and decreased rates of contraction and relaxation
compared to control animals. Cardiomyocytes isolated from transgenic
animals had lower basal levels of intracellular free Ca2+ and a
reduced rise in free Ca2+ following depolarization. After
stimulation, intracellular free Ca2+ returned to basal levels faster
in transgenic cells than in cells from control animals. These data
demonstrate that the overexpression of annexin VI in heart disrupts
normal Ca2+ homeostasis and suggests that this dysfunction may be due
to annexin VI regulation of pumps and/or exchangers in the membranes
of cardiomyocytes.
Received 28 June 1995; accepted in final form 6 September 1995.
APS Manuscript Number H591-5.
Article publication pending Am. J. Physiol. (Heart Circ. Physiology).
ISSN 1080-4757 Copyright 1995 The American Physiological Society.
Published in APStracts on 31 October 95