Targeted inhibition of activin receptor-like kinase 5 signaling attenuates cardiac dysfunction following myocardial infarction.
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 mg.kg(-1).day(-1) 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.
Department of Medicine, St. Vincent's Hospital, 29 Regent St., Fitzroy, Victoria 3065, Australia.
Sih Min
SM
Tan
Yuan
Y
Zhang
Kim A
KA
Connelly
Richard E
RE
Gilbert
Darren J
DJ
Kelly
D000199:Actins / Q000096:biosynthesis; D000818:Animals; D015703:Antigens, CD / Q000378:metabolism; D015214:Antigens, Differentiation, Myelomonocytic / Q000378:metabolism; D001549:Benzamides / Q000494:pharmacology*; D015153:Blotting, Western; D048429:Cell Size; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005109:Extracellular Matrix / Q000378:metabolism / Q000648:ultrastructure; D006321:Heart / Q000187:drug effects* / Q000503:physiopathology*; D007150:Immunohistochemistry; D008297:Male; D009203:Myocardial Infarction / Q000000981:diagnostic imaging / Q000188:drug therapy* / Q000503:physiopathology*; D009206:Myocardium / Q000378:metabolism / Q000473:pathology; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000648:ultrastructure; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors*; D011720:Pyrazoles / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D000077293:Receptor, Transforming Growth Factor-beta Type I; D018125:Receptors, Transforming Growth Factor beta / Q000037:antagonists & inhibitors*; D051899:Smad2 Protein / Q000096:biosynthesis; D016212:Transforming Growth Factor beta / Q000378:metabolism; D014463:Ultrasonography; D000097382:CD68 Molecule
D000199:Actins; D015703:Antigens, CD; D015214:Antigens, Differentiation, Myelomonocytic; D001549:Benzamides; D004791:Enzyme Inhibitors; D017346:Protein Serine-Threonine Kinases; D011720:Pyrazoles; D000077293:Receptor, Transforming Growth Factor-beta Type I; D018125:Receptors, Transforming Growth Factor beta; D051899:Smad2 Protein; D016212:Transforming Growth Factor beta; C509927:4-(4-(3-(pyridin-2-yl)-1H-pyrazol-4-yl)pyridin-2-yl)-N-(tetrahydro-2H-pyran-4-yl)benzamide; C067980:CD68 antigen, human; D000097382:CD68 Molecule; C497784:Smad2 protein, rat; C000625841:TGFBR1 protein, human; C000625843:Tgfbr1 protein, rat