title: Resveratrol reverses monocrotaline-induced pulmonary vascular and cardiac dysfunction: a potential role for atrogin-1 in smooth muscle.
abstract: 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.
authors.affiliation: College of Pharmacy, Division of Pharmaceutical Sciences, University of New Mexico Health Sciences Center, Albuquerque, NM 87131-0001, USA.
authors.forename: Michael L
authors.initials: ML
authors.lastname: Paffett
authors.forename: Selita N
authors.initials: SN
authors.lastname: Lucas
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Campen
mesh_terms: D056151:Airway Remodeling / Q000187:drug effects / Q000235:genetics / Q000502:physiology; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects / Q000502:physiology; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D004347:Drug Interactions; D006801:Humans; D006976:Hypertension, Pulmonary / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology; D006984:Hypertrophy / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology; D017380:Hypertrophy, Right Ventricular / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology; D051666:Kv1.5 Potassium Channel / Q000378:metabolism; D008297:Male; D016686:Monocrotaline / Q000494:pharmacology*; D009124:Muscle Proteins / Q000235:genetics / Q000378:metabolism*; D009131:Muscle, Smooth, Vascular / Q000187:drug effects* / Q000378:metabolism / Q000503:physiopathology; D032389:Myocytes, Smooth Muscle / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism; D011498:Protein Precursors / Q000235:genetics / Q000378:metabolism; D011651:Pulmonary Artery / Q000187:drug effects* / Q000378:metabolism / Q000503:physiopathology; D012333:RNA, Messenger / Q000187:drug effects / Q000235:genetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D000077185:Resveratrol; D044843:SKP Cullin F-Box Protein Ligases / Q000235:genetics / Q000378:metabolism*; D056564:Sirtuin 1 / Q000378:metabolism; D013267:Stilbenes / Q000494:pharmacology*; D000070584:Tripartite Motif Proteins; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism; D014452:Ubiquitins / Q000235:genetics / Q000378:metabolism; D020257:Ventricular Remodeling / Q000187:drug effects / Q000235:genetics / Q000502:physiology
chemical_list: D051666:Kv1.5 Potassium Channel; D009124:Muscle Proteins; D011498:Protein Precursors; D012333:RNA, Messenger; D013267:Stilbenes; D000070584:Tripartite Motif Proteins; D014452:Ubiquitins; C045677:ubiquitin precursor; D016686:Monocrotaline; D052250:Nitric Oxide Synthase Type III; C496316:Nos3 protein, rat; C486692:Fbxo32 protein, rat; D044843:SKP Cullin F-Box Protein Ligases; C499086:Trim63 protein, rat; D044767:Ubiquitin-Protein Ligases; C488368:Sirt1 protein, rat; D056564:Sirtuin 1; D000077185:Resveratrol