Resveratrol prevents monocrotaline-induced pulmonary hypertension in rats.
Proliferation of pulmonary arterial smooth muscle cells, endothelial dysfunction, oxidative stress, and inflammation promotes the development of pulmonary hypertension. Resveratrol is a polyphenolic compound that exerts antioxidant and anti-inflammatory protective effects in the systemic circulation, but its effects on pulmonary arteries remain poorly defined. The present study was undertaken to investigate the efficacy of resveratrol to prevent pulmonary hypertension. Rats injected with monocrotaline progressively developed pulmonary hypertension. Resveratrol treatment (25 mg/kg per day, PO, from day 1 postmonocrotaline) attenuated right ventricular systolic pressure and pulmonary arterial remodeling, decreased expression of inflammatory cytokines (tumor necrosis factor-alpha, interleukin 1beta, interleukin 6, and platelet-derived growth factor-alpha/beta), and limited leukocyte infiltration in the lung. Resveratrol also inhibited proliferation of pulmonary arterial smooth muscle cells. Treatment of rats with resveratrol increased expression of endothelial NO synthase, decreased oxidative stress, and improved endothelial function in small pulmonary arteries. Pulmonary hypertension was associated with an upregulation of NAD(P)H oxidase in small pulmonary arteries, which was significantly attenuated by resveratrol treatment. Our studies show that resveratrol exerts anti-inflammatory, antioxidant, and antiproliferative effects in the pulmonary arteries, which may contribute to the prevention of pulmonary hypertension.
Csiszar
Anna
A
Reynolds Oklahoma Center on Aging, Department of Geriatric Medicine, University of Oklahoma Health Science Center, Oklahoma City, OK 73104, USA.
Labinskyy
Nazar
N
Olson
Susan
S
Pinto
John T
JT
Gupte
Sachin
S
Wu
Joseph M
JM
Hu
Furong
F
Ballabh
Praveen
P
Podlutsky
Andrej
A
Losonczy
Gyorgy
G
de Cabo
Rafael
R
Mathew
Rajamma
R
Wolin
Michael S
MS
Ungvari
Zoltan
Z
D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D015153:Blotting, Western; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D004730:Endothelium, Vascular / Q000187:drug effects / Q000503:physiopathology; D015870:Gene Expression / Q000187:drug effects; D006976:Hypertension, Pulmonary / Q000139:chemically induced / Q000503:physiopathology / Q000517:prevention & control*; D015850:Interleukin-6 / Q000235:genetics; D008297:Male; D016686:Monocrotaline; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II / Q000235:genetics; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects; D011651:Pulmonary Artery / Q000187:drug effects* / Q000378:metabolism / Q000503:physiopathology; D051381:Rats; D017207:Rats, Sprague-Dawley; D000077185:Resveratrol; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013267:Stilbenes / Q000494:pharmacology*; D048069:Tumor Necrosis Factors / Q000235:genetics; D014664:Vasodilation / Q000187:drug effects; D014665:Vasodilator Agents / Q000494:pharmacology
D015850:Interleukin-6; D013267:Stilbenes; D048069:Tumor Necrosis Factors; D014665:Vasodilator Agents; D016686:Monocrotaline; D052247:Nitric Oxide Synthase Type II; D052250:Nitric Oxide Synthase Type III; D000077185:Resveratrol