Integrin binding angiopoietin-1 monomers reduce cardiac hypertrophy.
Angiopoietins were thought to be endothelial cell-specific via the tie2 receptor. We showed that angiopoietin-1 (ang1) also interacts with integrins on cardiac myocytes (CMs) to increase survival. Because ang1 monomers bind and activate integrins (not tie2), we determined their function in vivo. We examined monomer and multimer expressions during physiological and pathological cardiac remodeling and overexpressed ang1 monomers in phenylephrine-induced cardiac hypertrophy. Cardiac ang1 levels (mRNA, protein) increased during postnatal development and decreased with phenylephrine-induced cardiac hypertrophy, whereas tie2 phosphorylations were unchanged. We found that most or all of the changes during cardiac remodeling were in monomers, offering an explanation for unchanged tie2 activity. Heart tissue contains abundant ang1 monomers and few multimers (Western blotting). We generated plasmids that produce ang1 monomers (ang1-256), injected them into mice, and confirmed cardiac expression (immunohistochemistry, RT-PCR). Ang1 monomers localize to CMs, smooth muscle cells, and endothelial cells. In phenylephrine-induced cardiac hypertrophy, ang1-256 reduced left ventricle (LV)/tibia ratios, fetal gene expressions (atrial and brain natriuretic peptides, skeletal actin, beta-myosin heavy chain), and fibrosis (collagen III), and increased LV prosurvival signaling (akt, MAPK(p42/44)), and AMPK(T172). However, tie2 phosphorylations were unchanged. Ang1-256 increased integrin-linked kinase, a key regulator of integrin signaling and cardiac health. Collectively, these results suggest a role for ang1 monomers in cardiac remodeling.
Dallabrida
Susan M
SM
Division of Vascular Biology, Children's Hospital, Boston, Massachusetts 02115, USA.
Ismail
Nesreen S
NS
Pravda
Elke A
EA
Parodi
Emily M
EM
Dickie
Renee
R
Durand
Ellen M
EM
Lai
Jean
J
Cassiola
Flavia
F
Rogers
Rick A
RA
Rupnick
Maria A
MA
D042683:Angiopoietin-1 / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D001483:Base Sequence; D006332:Cardiomegaly / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism / Q000517:prevention & control*; D002460:Cell Line; D017931:DNA Primers / Q000235:genetics; D042783:Endothelial Cells / Q000378:metabolism; D016023:Integrins / Q000378:metabolism*; D020935:MAP Kinase Signaling System; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D032383:Myocytes, Cardiac / Q000378:metabolism; D010656:Phenylephrine / Q000633:toxicity; D010766:Phosphorylation; D011485:Protein Binding; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D020836:Protein Structure, Quaternary; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D042787:Receptor, TIE-2 / Q000378:metabolism; D011994:Recombinant Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D020257:Ventricular Remodeling / Q000235:genetics / Q000502:physiology; D000099200:Scaffold Protein ILK
D042683:Angiopoietin-1; D017931:DNA Primers; D016023:Integrins; D010656:Phenylephrine; D017346:Protein Serine-Threonine Kinases; D012333:RNA, Messenger; D042787:Receptor, TIE-2; D011994:Recombinant Proteins; D000099200:Scaffold Protein ILK; C467628:Angpt1 protein, mouse