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. 2017 May;32(5):628-636.
doi: 10.1007/s00380-017-0955-x. Epub 2017 Feb 17.

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

Kevin J Morine  1 , Xiaoying Qiao  1 , Vikram Paruchuri  1 , Mark J Aronovitz  1 , Emily E Mackey  1 , Lyanne Buiten  1 , Jonathan Levine  1 , Keshan Ughreja  1 , Prerna Nepali  1 , Robert M Blanton  1 , Richard H Karas  1 , S Paul Oh  2 , Navin K Kapur  3
Affiliations

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

Kevin J Morine et al. Heart Vessels. 2017 May.

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.

Keywords: Activin like kinase 1; Hereditary hemorrhagic telangiectasia; High output heart failure.

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Conflict of interest statement

Conflict of Interest

The authors declare they have no conflict of interest.

Figures

Fig 1
Fig 1. Phenotype of total body ALK-1 depletion
ALK-1 cKO mice treated with tamoxifen developed (A) colonic hemorrhage observed 13 days after tamoxifen treatment, (B) pale paws observed 10 days after Tamoxifen treatment, melena, and guaiac positive stool. (C) Compared to vehicle treated controls (cKO-CON), cKO-TAM mice demonstrated early mortality and a corresponding reduction in LV fractional shortening. *, p
Fig 2
Fig 2. ALK-1 depletion promotes high output heart failure
(A) Representative pressure volume loops demonstrate lower LV systolic pressure and increased LV end-systolic and end-diastolic volumes in cKO-TAM compared to cKO-CON mice after 14 days after tamoxifen treatment. Solid line indicates the end systolic pressure volume relationship. Echocardiography showed (B) increased LV end-systolic diameter beginning 7 days after treatment in cKO-TAM, not cKO-CON mice. *, p
Fig 3
Fig 3. Left ventricular expression of TGF-β family receptors and ligands
Compared to cKO-CON, cKO-TAM mice demonstrated (A) reduced mRNA levels of ALK-1 in the LV at 14 days after tamoxifen treatment. No change in (B–E) ALK-5, Endoglin, TGF-β1, BMP-7 or BMP-9 were observed in the cKO-TAM LV. *, p
Fig 4
Fig 4. ALK-1 depletion is associated with cardiomyocyte hypertrophy
Compared to cKO-CON, cKO-TAM mice demonstrated (A–B) increased cardiomyocyte cross-sectional area, (C) increased levels of BNP mRNA in the LV, and no change in LV levels of (D) β-MHC or (E) SERCA mRNA at 14 days after tamoxifen treatment. *, p
Fig 5
Fig 5. ALK-1 depletion is not associated with cardiac fibrosis
Compared to cKO-CON, cKO-TAM mice demonstrated no change in (A–B) collagen abundance with picrosirius red staining or (C–E) LV levels of Type I collagen, connective tissue growth factor (CTGF), or plasminogen activator inhibitor-1 (PAI-1) mRNA at 14 days after tamoxifen treatment.
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