Published online before print August 31, 2006, doi: 10.1161/01.RES.0000243978.15182.c1
© 2006 American Heart Association, Inc.
Integrative Physiology |
Reduced Cardiac L-Type Ca2+ Current in Cavß2–/– Embryos Impairs Cardiac Development and Contraction With Secondary Defects in Vascular Maturation
From Experimentelle und Klinische Pharmakologie und Toxikologie (P.W., B.H., V.F., M.F.), Universität des Saarlandes, Homburg, Germany; Institut für Kreislaufforschung und Sportmedizin (W.B.), Molekulare und Zelluläre Sportmedizin, Deutsche Sporthochschule, Köln, Germany; Institut für Molekulare Zellbiologie (L.K., P.L.), Universität des Saarlandes, Homburg, Germany; MGH Cardiovascular Research Center/Harvard Medical School, Massachusetts General Hospital (K.R.C.), Boston; and Institut für Physiologie I (B.K.F.), Rheinische Friedrich Wilhelms Universität, 53119 Bonn, Germany.
Correspondence to Marc Freichel and Veit Flockerzi, Experimentelle und Klinische Pharmakologie und Toxikologie, Universität des Saarlandes, 66421 Homburg, Germany. E-mail ptmfre{at}uniklinikum-saarland.de, ptvflo@uniklinikum-saarland.de
Cardiac myocyte contraction depends on transmembrane L-type Ca2+ currents and the ensuing release of Ca2+ from the sarcoplasmic reticulum. Here we show that these L-type Ca2+ currents are essential for cardiac pump function in the mouse at developmental stages where the functional significance of the heart becomes imperative to blood flow and to the continuing growth and survival of the embryo. Disruption of the Cavß2 gene, which encodes for the predominant ancillary ß subunit of cardiac Ca2+ channels, resulted in diminished L-type Ca2+ currents in cardiomyocytes of embryonic day 9.5 (E9.5). This led to a functionally compromised heart, causing defective remodeling of intra- and extraembryonic blood vessels and embryonic death following E10.5. The defects in vascular remodeling were also observed when the Cavß2 gene was selectively targeted in cardiomyocytes, demonstrating that they are secondary to cardiac failure rather than a result of the lack of Cavß2 proteins in the vasculature. Partial rescue of the Ca2+ channel currents by a Ca2+ channel agonist significantly postponed embryonic death in Cavß2–/– mice. Taken together, these data strongly support the essential role of L-type Ca2+ channel activity in cardiomyocytes for normal heart development and function and that this is a prerequisite for proper maturation of the vasculature.
Key Words: L-type Ca2+ channel • cardiac development • Cavß2 subunit • heart failure • embryonic death
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