Targeted inhibition of activin receptor-like kinase 5 signaling attenuates cardiac dysfunction following myocardial infarction.

Abstract

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.

• Authors: Sih Min Tan, Yuan Zhang, Kim A Connelly, Richard E Gilbert, Darren J Kelly
• Journal: American journal of physiology. Heart and circulatory physiology (Am J Physiol Heart Circ Physiol) Vol. 298 Issue 5 Pg. H1415-25 (May 2010) ISSN: 1522-1539 [Electronic] United States
• PMID: 20154262 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• 4-(4-(3-(pyridin-2-yl)-1H-pyrazol-4-yl)pyridin-2-yl)-N-(tetrahydro-2H-pyran-4-yl)benzamide
• Actins
• Antigens, CD
• Antigens, Differentiation, Myelomonocytic
• Benzamides
• CD68 antigen, human
• Enzyme Inhibitors
• Pyrazoles
• Receptors, Transforming Growth Factor beta
• Smad2 Protein
• Smad2 protein, rat
• Transforming Growth Factor beta
• Protein Serine-Threonine Kinases
• Receptor, Transforming Growth Factor-beta Type I
• TGFBR1 protein, human
• Tgfbr1 protein, rat

Topics

• Actins (biosynthesis)
• Animals
• Antigens, CD (metabolism)
• Antigens, Differentiation, Myelomonocytic (metabolism)
• Benzamides (pharmacology)
• Blotting, Western
• Cell Size
• Enzyme Inhibitors (pharmacology)
• Extracellular Matrix (metabolism, ultrastructure)
• Heart (drug effects, physiopathology)
• Immunohistochemistry
• Male
• Myocardial Infarction (diagnostic imaging, drug therapy, physiopathology)
• Myocardium (metabolism, pathology)
• Myocytes, Cardiac (drug effects, ultrastructure)
• Protein Serine-Threonine Kinases (antagonists & inhibitors)
• Pyrazoles (pharmacology)
• Rats
• Rats, Sprague-Dawley
• Receptor, Transforming Growth Factor-beta Type I
• Receptors, Transforming Growth Factor beta (antagonists & inhibitors)
• Smad2 Protein (biosynthesis)
• Transforming Growth Factor beta (metabolism)
• Ultrasonography