title: The TGF-β pathway mediates doxorubicin effects on cardiac endothelial cells.
abstract: Elevated ALK4/5 ligands including TGF-β and activins have been linked to cardiovascular remodeling and heart failure. Doxorubicin (Dox) is commonly used as a model of cardiomyopathy, a condition that often precedes cardiovascular remodeling and heart failure. In 7-8-week-old C57Bl/6 male mice treated with Dox we found decreased capillary density, increased levels of ALK4/5 ligand and Smad2/3 transcripts, and increased expression of Smad2/3 transcriptional targets. Human cardiac microvascular endothelial cells (HCMVEC) treated with Dox also showed increased levels of ALK4/5 ligands, Smad2/3 transcriptional targets, a decrease in proliferation and suppression of vascular network formation in a HCMVEC and human cardiac fibroblasts co-culture assay. Our hypothesis is that the deleterious effects of Dox on endothelial cells are mediated in part by the activation of the TGF-β pathway. We used the inhibitor of ALK4/5 kinases SB431542 (SB) in concert with Dox to ascertain the role of TGF-β pathway activation in doxorubicin induced endothelial cell defects. SB prevented the suppression of HCMVEC proliferation in the presence of TGF-β2 and activin A, and alleviated the inhibition of HCMVEC proliferation by Dox. SB also prevented the suppression of vascular network formation in co-cultures of HCMVEC and human cardiac fibroblasts treated with Dox. Our results show that the inhibition of the TGF-β pathway alleviates the detrimental effects of Dox on endothelial cells in vitro.
authors.affiliation: College of Pharmacy, University of Hawaii-Hilo, USA.
authors.forename: Zuyue
authors.initials: Z
authors.lastname: Sun
authors.affiliation: Division of Basic Sciences, Kansas City University, USA.
authors.forename: Jill
authors.initials: J
authors.lastname: Schriewer
authors.affiliation: Center for Cardiovascular Research, John A. Burns School of Medicine, University of Hawaii-Manoa, USA.
authors.forename: Mingxin
authors.initials: M
authors.lastname: Tang
authors.affiliation: Division of Basic Sciences, Kansas City University, USA.
authors.forename: Jerry
authors.initials: J
authors.lastname: Marlin
authors.affiliation: College of Pharmacy, University of Hawaii-Hilo, USA.
authors.forename: Frederick
authors.initials: F
authors.lastname: Taylor
authors.affiliation: Center for Cardiovascular Research, John A. Burns School of Medicine, University of Hawaii-Manoa, USA.
authors.forename: Ralph V
authors.initials: RV
authors.lastname: Shohet
authors.affiliation: Division of Basic Sciences, Kansas City University, USA. Electronic address: ekonorev@kcumb.edu.
authors.forename: Eugene A
authors.initials: EA
authors.lastname: Konorev
mesh_terms: D030201:Activin Receptors, Type I / Q000235:genetics / Q000378:metabolism; D028341:Activins / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology; D000818:Animals; D001549:Benzamides / Q000494:pharmacology; D002460:Cell Line; D018920:Coculture Techniques; D004149:Dioxoles / Q000494:pharmacology; D004317:Doxorubicin / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D042783:Endothelial Cells / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D005347:Fibroblasts / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D005786:Gene Expression Regulation; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009206:Myocardium / Q000166:cytology / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism; D000077293:Receptor, Transforming Growth Factor-beta Type I; D018125:Receptors, Transforming Growth Factor beta / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D051899:Smad2 Protein / Q000235:genetics / Q000378:metabolism; D051900:Smad3 Protein / Q000235:genetics / Q000378:metabolism; D053781:Transforming Growth Factor beta2 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology*
chemical_list: C459179:4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide; D001549:Benzamides; D004149:Dioxoles; D018125:Receptors, Transforming Growth Factor beta; C497782:SMAD2 protein, human; C497790:SMAD3 protein, human; D051899:Smad2 Protein; D051900:Smad3 Protein; D053781:Transforming Growth Factor beta2; C422405:activin A; D028341:Activins; D004317:Doxorubicin; D017346:Protein Serine-Threonine Kinases; C498932:ACVR1B protein, human; D030201:Activin Receptors, Type I; D000077293:Receptor, Transforming Growth Factor-beta Type I
keywords: Angiogenesis; Anthracyclines; Cardiomyopathy; Endothelial cells; TGF-β