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Erschienen in: Heart and Vessels 5/2017

17.02.2017 | Original Article

Conditional knockout of activin like kinase-1 (ALK-1) leads to heart failure without maladaptive remodeling

verfasst von: Kevin J. Morine, Xiaoying Qiao, Vikram Paruchuri, Mark J. Aronovitz, Emily E. Mackey, Lyanne Buiten, Jonathan Levine, Keshan Ughreja, Prerna Nepali, Robert M. Blanton, Richard H. Karas, S. Paul Oh, Navin K. Kapur

Erschienen in: Heart and Vessels | Ausgabe 5/2017

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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.
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Metadaten
Titel
Conditional knockout of activin like kinase-1 (ALK-1) leads to heart failure without maladaptive remodeling
verfasst von
Kevin J. Morine
Xiaoying Qiao
Vikram Paruchuri
Mark J. Aronovitz
Emily E. Mackey
Lyanne Buiten
Jonathan Levine
Keshan Ughreja
Prerna Nepali
Robert M. Blanton
Richard H. Karas
S. Paul Oh
Navin K. Kapur
Publikationsdatum
17.02.2017
Verlag
Springer Japan
Erschienen in
Heart and Vessels / Ausgabe 5/2017
Print ISSN: 0910-8327
Elektronische ISSN: 1615-2573
DOI
https://doi.org/10.1007/s00380-017-0955-x

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