A lethal perinatal cardiac phenotype resulting from altered integrin function in cardiomyocytes.
BACKGROUND
Integrins are heterodimeric receptors that couple the extracellular matrix to intracellular signaling pathways and the cyoskeleton. Integrins are strain transducers and candidates for modulators or effectors of cardiac hypertrophy.


METHODS
To begin to probe this function, we have transgenically expressed a chimeric protein that alters integrin function in cardiomyocytes. The transgene (Tac-beta(1D)) consists of the biologically inert extracellular and transmembrane domain of the interleukin-2 receptor alpha subunit (Tac) fused to the cytoplasmic tail of the human beta(1D) integrin driven by the cardiac alpha-myosin heavy chain promoter. Transgene expression results in a severe, usually fatal, perinatal cardiac phenotype, characterized by initial electrocardiographic abnormalities followed by extensive myocyte loss, macrophage infiltration, and replacement fibrosis.


RESULTS
Expression of Tac-beta(1D) resulted in displacement of endogenous beta(1D) integrin from Z-lines and T-tubules, decreased expression of endogenous beta(1D), and disrupted the fibronectin pericellular matrix. These results are consistent with an essential role for beta(1) integrins in maintenance of cardiomyocyte viability and interaction with extracellular matrix.


CONCLUSIONS
The appearance of conduction abnormalities before morphologic changes suggests that integrins are important in the development or maintenance of the conducting system of the heart.
Valencik
Maria L
ML
Department of Internal Medicine, University of Utah School of Medicine, Salt Lake City, Utah 84132, USA.
Keller
Rebecca S
RS
Loftus
Joseph C
JC
McDonald
John A
JA
D000818:Animals; D000831:Animals, Newborn / Q000235:genetics; D004195:Disease Models, Animal; D004562:Electrocardiography; D005109:Extracellular Matrix / Q000235:genetics / Q000648:ultrastructure; D005260:Female; D005353:Fibronectins / Q000096:biosynthesis / Q000235:genetics; D005786:Gene Expression Regulation / Q000235:genetics; D005804:Genes, Lethal / Q000235:genetics*; D006325:Heart Atria / Q000002:abnormalities / Q000166:cytology / Q000648:ultrastructure; D006329:Heart Conduction System / Q000002:abnormalities / Q000166:cytology / Q000503:physiopathology; D006352:Heart Ventricles / Q000002:abnormalities / Q000166:cytology / Q000648:ultrastructure; D019012:Integrin beta1 / Q000096:biosynthesis* / Q000235:genetics*; D008297:Male; D051379:Mice / Q000235:genetics; D008822:Mice, Transgenic / Q000235:genetics; D008955:Models, Cardiovascular; D032383:Myocytes, Cardiac / Q000378:metabolism*; D010641:Phenotype; D011993:Recombinant Fusion Proteins / Q000096:biosynthesis / Q000235:genetics; D012720:Severity of Illness Index
D005353:Fibronectins; D019012:Integrin beta1; D011993:Recombinant Fusion Proteins