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

Feb 16, 2010American journal of physiology. Heart and circulatory physiology

Blocking a specific cell signal reduces heart problems after a heart attack

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Abstract

Treatment with the TGF-beta type I receptor inhibitor GW788388 significantly reduced TGF-beta activity and improved cardiac function in rats following myocardial infarction.

Myocardial infarction induced systolic dysfunction and pathological changes in the heart, including myofibroblast accumulation and collagen deposition.
Administration of GW788388 reduced the activation of Smad2, a key signaling protein associated with TGF-beta activity.
The treatment also decreased alpha-smooth muscle actin levels, which are indicative of myofibroblast presence.
Collagen I deposition in the noninfarct zone was significantly reduced with GW788388 treatment.
Cardiomyocyte hypertrophy, a response to cardiac stress, was attenuated by inhibiting TGF-beta signaling.

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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.

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

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