title: Conditional knockout of activin like kinase-1 (ALK-1) leads to heart failure without maladaptive remodeling.
abstract: Activin like kinase-1 (AlK-1) mediates signaling via the transforming growth factor beta (TGFβ) family of ligands. AlK-1 activity promotes endothelial proliferation and migration. Reduced AlK-1 activity is associated with arteriovenous malformations. No studies have examined the effect of global AlK-1 deletion on indices of cardiac remodeling. We hypothesized that reduced levels of AlK-1 promote maladaptive cardiac remodeling. To test this hypothesis, we employed AlK-1 conditional knockout mice (cKO) harboring the ROSA26-CreER knock-in allele, whereby a single dose of intraperitoneal tamoxifen triggered ubiquitous Cre recombinase-mediated excision of floxed AlK-1 alleles. Tamoxifen treated wild-type (WT-TAM; n = 5) and vehicle treated AlK-1-cKO mice (cKO-CON; n = 5) served as controls for tamoxifen treated AlK-1-cKO mice (cKO-TAM; n = 15). AlK-1 cKO-TAM mice demonstrated reduced 14-day survival compared to cKO-CON controls (13 vs 100%, respectively, p < 0.01). Seven days after treatment, cKO-TAM mice exhibited reduced left ventricular (LV) fractional shortening, progressive LV dilation, and gastrointestinal bleeding. After 14 days total body mass was reduced, but LV and lung mass increased in cKO-TAM not cKO-CON mice. Peak LV systolic pressure, contractility, and arterial elastance were reduced, but LV end-diastolic pressure and stroke volume were increased in cKO-TAM, not cKO-CON mice. LV AlK-1 mRNA levels were reduced in cKO-TAM, not cKO-CON mice. LV levels of other TGFβ-family ligands and receptors (AlK5, TBRII, BMPRII, Endoglin, BMP7, BMP9, and TGFβ1) were unchanged between groups. Cardiomyocyte area and LV levels of BNP were increased in cKO-TAM mice, but LV levels of β-MHC and SERCA were unchanged. No increase in markers of cardiac fibrosis, Type I collagen, CTGF, or PAI-1, were observed between groups. No differences were observed for any variable studied between cKO-CON and WT-TAM mice. Global deletion of AlK-1 is associated with the development of high output heart failure without maladaptive remodeling. Future studies exploring the functional role of AlK-1 in cardiac remodeling independent of systemic AVMs are required.
authors.affiliation: Molecular Cardiology Research Institute and Division of Cardiology, Department of Medicine, Tufts Medical Center, 800 Washington Street, Boston, MA, 02111, USA.
authors.forename: Kevin J
authors.initials: KJ
authors.lastname: Morine
authors.affiliation: Molecular Cardiology Research Institute and Division of Cardiology, Department of Medicine, Tufts Medical Center, 800 Washington Street, Boston, MA, 02111, USA.
authors.forename: Xiaoying
authors.initials: X
authors.lastname: Qiao
authors.affiliation: Molecular Cardiology Research Institute and Division of Cardiology, Department of Medicine, Tufts Medical Center, 800 Washington Street, Boston, MA, 02111, USA.
authors.forename: Vikram
authors.initials: V
authors.lastname: Paruchuri
authors.affiliation: Molecular Cardiology Research Institute and Division of Cardiology, Department of Medicine, Tufts Medical Center, 800 Washington Street, Boston, MA, 02111, USA.
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Aronovitz
authors.affiliation: Molecular Cardiology Research Institute and Division of Cardiology, Department of Medicine, Tufts Medical Center, 800 Washington Street, Boston, MA, 02111, USA.
authors.forename: Emily E
authors.initials: EE
authors.lastname: Mackey
authors.affiliation: Molecular Cardiology Research Institute and Division of Cardiology, Department of Medicine, Tufts Medical Center, 800 Washington Street, Boston, MA, 02111, USA.
authors.forename: Lyanne
authors.initials: L
authors.lastname: Buiten
authors.affiliation: Molecular Cardiology Research Institute and Division of Cardiology, Department of Medicine, Tufts Medical Center, 800 Washington Street, Boston, MA, 02111, USA.
authors.forename: Jonathan
authors.initials: J
authors.lastname: Levine
authors.affiliation: Molecular Cardiology Research Institute and Division of Cardiology, Department of Medicine, Tufts Medical Center, 800 Washington Street, Boston, MA, 02111, USA.
authors.forename: Keshan
authors.initials: K
authors.lastname: Ughreja
authors.affiliation: Molecular Cardiology Research Institute and Division of Cardiology, Department of Medicine, Tufts Medical Center, 800 Washington Street, Boston, MA, 02111, USA.
authors.forename: Prerna
authors.initials: P
authors.lastname: Nepali
authors.affiliation: Molecular Cardiology Research Institute and Division of Cardiology, Department of Medicine, Tufts Medical Center, 800 Washington Street, Boston, MA, 02111, USA.
authors.forename: Robert M
authors.initials: RM
authors.lastname: Blanton
authors.affiliation: Molecular Cardiology Research Institute and Division of Cardiology, Department of Medicine, Tufts Medical Center, 800 Washington Street, Boston, MA, 02111, USA.
authors.forename: Richard H
authors.initials: RH
authors.lastname: Karas
authors.affiliation: Department of Physiology and Functional Genomics, University of Florida, 1345 Center Drive, Gainesville, FL, 32610-0274, USA.
authors.forename: S Paul
authors.initials: SP
authors.lastname: Oh
authors.affiliation: Molecular Cardiology Research Institute and Division of Cardiology, Department of Medicine, Tufts Medical Center, 800 Washington Street, Boston, MA, 02111, USA. Nkapur@tuftsmedicalcenter.org.
authors.forename: Navin K
authors.initials: NK
authors.lastname: Kapur
mesh_terms: D030201:Activin Receptors, Type I / Q000096:biosynthesis / Q000235:genetics*; D030301:Activin Receptors, Type II; D000483:Alleles; D000818:Animals; D004195:Disease Models, Animal; D018450:Disease Progression; D005786:Gene Expression Regulation; D006333:Heart Failure / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology; D018345:Mice, Knockout; D012313:RNA / Q000235:genetics*; D060888:Real-Time Polymerase Chain Reaction; D015398:Signal Transduction; D016277:Ventricular Function, Left / Q000502:physiology*; D020257:Ventricular Remodeling / Q000502:physiology*
chemical_list: D012313:RNA; D030201:Activin Receptors, Type I; D030301:Activin Receptors, Type II; C498931:Acvrl1 protein, mouse
keywords: Activin like kinase 1; Hereditary hemorrhagic telangiectasia; High output heart failure