Kevin J Morine1, Xiaoying Qiao1, Vikram Paruchuri1, Mark J Aronovitz1, Emily E Mackey1, Lyanne Buiten1, Jonathan Levine1, Keshan Ughreja1, Prerna Nepali1, Robert M Blanton1, S Paul Oh2, Richard H Karas1, Navin K Kapur3. 1. Molecular Cardiology Research Institute and Division of Cardiology, Department of Medicine, Tufts Medical Center, 800 Washington Street, Boston, MA, 02111, USA. 2. Department of Physiology and Functional Genomics, University of Florida College of Medicine, 1600 SW Archer Road, Gainesville, FL 32610, USA. 3. Molecular Cardiology Research Institute and Division of Cardiology, Department of Medicine, Tufts Medical Center, 800 Washington Street, Boston, MA, 02111, USA. Electronic address: Nkapur@tuftsmedicalcenter.org.
Abstract
INTRODUCTION: Activin receptor-like kinase 1 (ALK1) mediates signaling via the transforming growth factor beta-1 (TGFβ1), a pro-fibrogenic cytokine. No studies have defined a role for ALK1 in heart failure. HYPOTHESIS: We tested the hypothesis that reduced ALK1 expression promotes maladaptive cardiac remodeling in heart failure. METHODS AND RESULTS: In patients with advanced heart failure referred for left ventricular (LV) assist device implantation, LV Alk1 mRNA and protein levels were lower than control LV obtained from patients without heart failure. To investigate the role of ALK1 in heart failure, Alk1 haploinsufficient (Alk1+/-) and wild-type (WT) mice were studied 2 weeks after severe transverse aortic constriction (TAC). LV and lung weights were higher in Alk1+/- mice after TAC. Cardiomyocyte area and LV mRNA levels of brain natriuretic peptide and β-myosin heavy chain were increased similarly in Alk1+/- and WT mice after TAC. Alk-1 mice exhibited reduced Smad 1 phosphorylation and signaling compared to WT mice after TAC. Compared to WT, LV fibrosis and Type 1 collagen mRNA and protein levels were higher in Alk1+/- mice. LV fractional shortening was lower in Alk1+/- mice after TAC. CONCLUSIONS: Reduced expression of ALK1 promotes cardiac fibrosis and impaired LV function in a murine model of heart failure. Further studies examining the role of ALK1 and ALK1 inhibitors on cardiac remodeling are required.
INTRODUCTION:Activin receptor-like kinase 1 (ALK1) mediates signaling via the transforming growth factor beta-1 (TGFβ1), a pro-fibrogenic cytokine. No studies have defined a role for ALK1 in heart failure. HYPOTHESIS: We tested the hypothesis that reduced ALK1 expression promotes maladaptive cardiac remodeling in heart failure. METHODS AND RESULTS: In patients with advanced heart failure referred for left ventricular (LV) assist device implantation, LV Alk1 mRNA and protein levels were lower than control LV obtained from patients without heart failure. To investigate the role of ALK1 in heart failure, Alk1 haploinsufficient (Alk1+/-) and wild-type (WT) mice were studied 2 weeks after severe transverse aortic constriction (TAC). LV and lung weights were higher in Alk1+/- mice after TAC. Cardiomyocyte area and LV mRNA levels of brain natriuretic peptide and β-myosin heavy chain were increased similarly in Alk1+/- and WT mice after TAC. Alk-1mice exhibited reduced Smad 1 phosphorylation and signaling compared to WT mice after TAC. Compared to WT, LV fibrosis and Type 1 collagen mRNA and protein levels were higher in Alk1+/- mice. LV fractional shortening was lower in Alk1+/- mice after TAC. CONCLUSIONS: Reduced expression of ALK1 promotes cardiac fibrosis and impaired LV function in a murine model of heart failure. Further studies examining the role of ALK1 and ALK1 inhibitors on cardiac remodeling are required.
Authors: Navin K Kapur; Szuhuei Wilson; Adil A Yunis; Xiaoying Qiao; Emily Mackey; Vikram Paruchuri; Corey Baker; Mark J Aronovitz; S Ananth Karumanchi; Michelle Letarte; David A Kass; Michael E Mendelsohn; Richard H Karas Journal: Circulation Date: 2012-05-16 Impact factor: 29.690
Authors: A Necchi; P Giannatempo; L Mariani; E Farè; D Raggi; M Pennati; N Zaffaroni; F Crippa; A Marchianò; N Nicolai; M Maffezzini; E Togliardi; M G Daidone; A M Gianni; R Salvioni; F De Braud Journal: Invest New Drugs Date: 2014-02-26 Impact factor: 3.850
Authors: M Simonelli; P Zucali; A Santoro; M B Thomas; F G de Braud; H Borghaei; J Berlin; C S Denlinger; C Noberasco; L Rimassa; T-Y Kim; P A English; A Abbattista; C Gallo Stampino; M Carpentieri; J A Williams Journal: Ann Oncol Date: 2016-06-20 Impact factor: 32.976
Authors: 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 Journal: Heart Vessels Date: 2017-02-17 Impact factor: 2.037
Authors: S P Oh; T Seki; K A Goss; T Imamura; Y Yi; P K Donahoe; L Li; K Miyazono; P ten Dijke; S Kim; E Li Journal: Proc Natl Acad Sci U S A Date: 2000-03-14 Impact factor: 11.205
Authors: Lukas J A C Hawinkels; Amaya Garcia de Vinuesa; Madelon Paauwe; Marianna Kruithof-de Julio; Eliza Wiercinska; Evangelia Pardali; Laura Mezzanotte; Stijn Keereweer; Tanya M Braumuller; Renier C Heijkants; Jos Jonkers; Clemens W Löwik; Marie-José Goumans; Timo L ten Hagen; Peter ten Dijke Journal: Clin Cancer Res Date: 2015-09-15 Impact factor: 12.531
Authors: Johanna C Bendell; Michael S Gordon; Herbert I Hurwitz; Suzanne F Jones; David S Mendelson; Gerard C Blobe; Neeraj Agarwal; Carolyn H Condon; Dawn Wilson; Amelia E Pearsall; Yijun Yang; Ty McClure; Kenneth M Attie; Matthew L Sherman; Sunil Sharma Journal: Clin Cancer Res Date: 2013-10-30 Impact factor: 12.531
Authors: Navin K Kapur; Vikram Paruchuri; Mark J Aronovitz; Xiaoying Qiao; Emily E Mackey; Gerard H Daly; Kishan Ughreja; Jonathan Levine; Robert Blanton; Nicholas S Hill; Richard H Karas Journal: PLoS One Date: 2013-07-30 Impact factor: 3.240
Authors: Carlos Martínez-Salgado; Fernando Sánchez-Juanes; Francisco J López-Hernández; José M Muñoz-Félix Journal: Front Pharmacol Date: 2022-06-13 Impact factor: 5.988
Authors: Kevin J Morine; Xiaoying Qiao; Sam York; Peter S Natov; Vikram Paruchuri; Yali Zhang; Mark J Aronovitz; Richard H Karas; Navin K Kapur Journal: Circulation Date: 2018-07-31 Impact factor: 29.690
Authors: Daniel A Richards; Mark J Aronovitz; Timothy D Calamaras; Kelly Tam; Gregory L Martin; Peiwen Liu; Heather K Bowditch; Phyllis Zhang; Gordon S Huggins; Robert M Blanton Journal: Sci Rep Date: 2019-04-10 Impact factor: 4.379
Authors: Agnes S Kim; Katharine J Henderson; Sumeet Pawar; Min Jung Kim; Shahnaz Punjani; Jeffrey S Pollak; John T Fahey; Guadalupe Garcia-Tsao; Lissa Sugeng; Lawrence H Young Journal: J Am Heart Assoc Date: 2020-10-15 Impact factor: 5.501