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. CONCLUSION: 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.
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. CONCLUSION: 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.
Authors: Laura A DiMichele; Jason T Doherty; Mauricio Rojas; Hilary E Beggs; Louis F Reichardt; Christopher P Mack; Joan M Taylor Journal: Circ Res Date: 2006-08-10 Impact factor: 17.367
Authors: Zeenat S Hakim; Laura A DiMichele; Jason T Doherty; Jonathon W Homeister; Hilary E Beggs; Louis F Reichardt; Robert J Schwartz; Joseph Brackhan; Oliver Smithies; Christopher P Mack; Joan M Taylor Journal: Mol Cell Biol Date: 2007-05-25 Impact factor: 4.272
Authors: Zeenat S Hakim; Laura A DiMichele; Mauricio Rojas; Dane Meredith; Christopher P Mack; Joan M Taylor Journal: J Mol Cell Cardiol Date: 2008-11-05 Impact factor: 5.000