Integrin-linked kinase, a novel component of the cardiac mechanical stretch sensor, controls contractility in the zebrafish heart.
The vertebrate heart possesses autoregulatory mechanisms enabling it first to sense and then to adapt its force of contraction to continually changing demands. The molecular components of the cardiac mechanical stretch sensor are mostly unknown but of immense medical importance, since dysfunction of this sensing machinery is suspected to be responsible for a significant proportion of human heart failure. In the hearts of the ethylnitros-urea (ENU)-induced, recessive embryonic lethal zebrafish heart failure mutant main squeeze (msq), we find stretch-responsive genes such as atrial natriuretic factor (anf) and vascular endothelial growth factor (vegf) severely down-regulated. We demonstrate through positional cloning that heart failure in msq mutants is due to a mutation in the integrin-linked kinase (ilk) gene. ILK specifically localizes to costameres and sarcomeric Z-discs. The msq mutation (L308P) reduces ILK kinase activity and disrupts binding of ILK to the Z-disc adaptor protein beta-parvin (Affixin). Accordingly, in msq mutant embryos, heart failure can be suppressed by expression of ILK, and also of a constitutively active form of Protein Kinase B (PKB), and VEGF. Furthermore, antisense-mediated abrogation of zebrafish beta-parvin phenocopies the msq phenotype. Thus, we provide evidence that the heart uses the Integrin-ILK-beta-parvin network to sense mechanical stretch and respond with increased expression of ANF and VEGF, the latter of which was recently shown to augment cardiac force by increasing the heart's calcium transients.
Bendig
Garnet
G
Department of Medicine III, University of Heidelberg, D-69120 Heidelberg, Germany.
Grimmler
Matthias
M
Huttner
Inken G
IG
Wessels
Georgia
G
Dahme
Tillman
T
Just
Steffen
S
Trano
Nicole
N
Katus
Hugo A
HA
Fishman
Mark C
MC
Rottbauer
Wolfgang
W
D000185:Actinin / Q000502:physiology; D000595:Amino Acid Sequence; D000818:Animals; D009320:Atrial Natriuretic Factor / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics; D002118:Calcium / Q000378:metabolism; D015536:Down-Regulation / Q000235:genetics; D005819:Genetic Markers; D006801:Humans; D040542:Mechanotransduction, Cellular / Q000235:genetics / Q000502:physiology*; D008969:Molecular Sequence Data; D009200:Myocardial Contraction / Q000235:genetics / Q000502:physiology*; D009206:Myocardium / Q000201:enzymology*; D017346:Protein Serine-Threonine Kinases / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D042461:Vascular Endothelial Growth Factor A / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics; D015027:Zebrafish / Q000196:embryology; D000099200:Scaffold Protein ILK
D000185:Actinin; D009320:Atrial Natriuretic Factor; D002118:Calcium; D005819:Genetic Markers; D017346:Protein Serine-Threonine Kinases; D042461:Vascular Endothelial Growth Factor A; D000099200:Scaffold Protein ILK