Document Detail

Targeted inhibition of activin receptor-like kinase 5 signaling attenuates cardiac dysfunction following myocardial infarction.
MedLine Citation:
PMID:  20154262     Owner:  NLM     Status:  MEDLINE    
Following myocardial infarction (MI), the heart undergoes a pathological process known as remodeling, which in many instances results in cardiac dysfunction and ultimately heart failure and death. Transforming growth factor-beta (TGF-beta) is a key mediator in the pathogenesis of cardiac remodeling following MI. We thus aimed to inhibit TGF-beta signaling using a novel orally active TGF-beta type I receptor [activin receptor-like kinase 5 (ALK5)] inhibitor (GW788388) to attenuate left ventricular remodeling and cardiac dysfunction in a rat model of MI. Sprague-Dawley rats underwent left anterior descending coronary artery ligation to induce experimental MI and then were randomized to receive GW788388 at a dosage of 50 or vehicle 1 wk after surgery. After 4 wk of treatment, echocardiography was performed before the rats were euthanized. Animals that received left anterior descending coronary artery ligation demonstrated systolic dysfunction, Smad2 activation, myofibroblasts accumulation, collagen deposition, and myocyte hypertrophy (all P < 0.05). Treatment with GW788388 significantly attenuated systolic dysfunction in the MI animals, together with the attenuation of the activated (phosphorylated) Smad2 (P < 0.01), alpha-smooth muscle actin (P < 0.001), and collagen I (P < 0.05) in the noninfarct zone of MI rats. Cardiomyocyte hypertrophy in MI hearts was also attenuated by ALK5 inhibition (P < 0.05). In brief, treatment with a novel TGF-beta type I receptor inhibitor, GW788388, significantly reduced TGF-beta activity, leading to the attenuation of systolic dysfunction and left ventricular remodeling in an experimental rat model of MI.
Sih Min Tan; Yuan Zhang; Kim A Connelly; Richard E Gilbert; Darren J Kelly
Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2010-02-12
Journal Detail:
Title:  American journal of physiology. Heart and circulatory physiology     Volume:  298     ISSN:  1522-1539     ISO Abbreviation:  Am. J. Physiol. Heart Circ. Physiol.     Publication Date:  2010 May 
Date Detail:
Created Date:  2010-05-05     Completed Date:  2010-05-18     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  100901228     Medline TA:  Am J Physiol Heart Circ Physiol     Country:  United States    
Other Details:
Languages:  eng     Pagination:  H1415-25     Citation Subset:  IM    
Department of Medicine, St. Vincent's Hospital, 29 Regent St., Fitzroy, Victoria 3065, Australia.
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MeSH Terms
Actins / biosynthesis
Antigens, CD / metabolism
Antigens, Differentiation, Myelomonocytic / metabolism
Benzamides / pharmacology*
Blotting, Western
Cell Size
Enzyme Inhibitors / pharmacology*
Extracellular Matrix / metabolism,  ultrastructure
Heart / drug effects*,  physiopathology*
Myocardial Infarction / drug therapy*,  physiopathology*,  ultrasonography
Myocardium / metabolism,  pathology
Myocytes, Cardiac / drug effects,  ultrastructure
Protein-Serine-Threonine Kinases / antagonists & inhibitors*
Pyrazoles / pharmacology*
Rats, Sprague-Dawley
Receptors, Transforming Growth Factor beta / antagonists & inhibitors*
Smad2 Protein / biosynthesis
Transforming Growth Factor beta / metabolism
Reg. No./Substance:
0/4-(4-(3-(pyridin-2-yl)-1H-pyrazol-4-yl)pyridin-2-yl)-N-(tetrahydro-2H-pyran-4-yl)benzamide; 0/Actins; 0/Antigens, CD; 0/Antigens, Differentiation, Myelomonocytic; 0/Benzamides; 0/CD68 antigen, human; 0/Enzyme Inhibitors; 0/Madh2 protein, rat; 0/Pyrazoles; 0/Receptors, Transforming Growth Factor beta; 0/Smad2 Protein; 0/Transforming Growth Factor beta; EC type I receptor; EC Kinases

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