Resveratrol reverses monocrotaline-induced pulmonary vascular and cardiac dysfunction: a potential role for atrogin-1 in smooth muscle.
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Arterial remodeling contributes to elevated pulmonary artery (PA) pressures and right ventricular hypertrophy seen in pulmonary hypertension (PH). Resveratrol, a sirtuin-1 (SIRT1) pathway activator, can prevent the development of PH in a commonly used animal model, but it is unclear whether it can reverse established PH pathophysiology. Furthermore, atrophic ubiquitin ligases, such as atrogin-1 and MuRF-1, are known to be induced by SIRT1 activators but have not been characterized in hypertrophic vascular disease. Therefore, we hypothesized that monocrotaline (MCT)-induced PH would attenuate atrophy pathways in the PA while, conversely, SIRT1 activation (resveratrol) would reverse indices of PH and restore atrophic gene expression. Thus, we injected Sprague-Dawley rats with MCT (50 mg/kg i.p.) or saline at Day 0, and then treated with oral resveratrol or sildenafil from days 28-42 post-MCT injection. Oral resveratrol attenuated established MCT-induced PH indices, including right ventricular systolic pressure, right ventricular hypertrophy, and medial thickening of intrapulmonary arteries. Resveratrol also normalized PA atrogin-1 mRNA expression, which was significantly reduced by MCT. In cultured human PA smooth muscle cells (hPASMC), resveratrol significantly inhibited PDGF-stimulated proliferation and cellular hypertrophy, which was also associated with improvements in atrogin-1 levels. In addition, SIRT1 inhibition augmented hPASMC proliferation, as assessed by DNA mass, and suppressed atrogin mRNA expression. These findings demonstrate an inverse relationship between indices of PH and PA atrogin expression that is SIRT1 dependent and may reflect a novel role for SIRT1 in PASMCs opposing cellular hypertrophy and proliferation.Copyright © 2011 Elsevier Inc. All rights reserved.
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keywords
Airway Remodeling
Animals
Blood Pressure
Cell Proliferation
Cells, Cultured
Drug Interactions
Humans
Hypertension, Pulmonary
Hypertrophy
Hypertrophy, Right Ventricular
Kv1.5 Potassium Channel
Male
Monocrotaline
Muscle Proteins
Muscle, Smooth, Vascular
Myocytes, Smooth Muscle
Nitric Oxide Synthase Type III
Protein Precursors
Pulmonary Artery
RNA, Messenger
Rats
Rats, Sprague-Dawley
SKP Cullin F-Box Protein Ligases
Sirtuin 1
Stilbenes
Ubiquitin-Protein Ligases
Ubiquitins
Ventricular Remodeling
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