Published online before print August 31, 2006, doi: 10.1161/01.RES.0000243978.15182.c1
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Submitted on April 4, 2006
Revised on July 13, 2006
Accepted on August 22, 2006
Reduced Cardiac L-Type Ca2+ Current in Cav
2-/- Embryos Impairs Cardiac Development and Contraction With Secondary Defects in Vascular Maturation
Petra Weissgerber ;
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; Massachusetts General Hospital (K.R.C.), Boston; and Institut für Physiologie I (B.K.F.), Rheinische Friedrich Wilhelms Universität, 53119 Bonn, Germany.
* To whom correspondence should be addressed. E-mail: ptmfre{at}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 Cav
2 gene, which encodes for the predominant ancillary 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 Cav2 gene was selectively targeted in cardiomyocytes, demonstrating that they are secondary to cardiac failure rather than a result of the lack of Cav2 proteins in the vasculature. Partial rescue of the Ca2+ channel currents by a Ca2+ channel agonist significantly postponed embryonic death in Cav2-/- 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 • Cav
2 subunit •
heart failure •
embryonic death
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