Resveratrol Prevents Monocrotaline-Induced Pulmonary Hypertension in Rats

Abstract

Abstract-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-␣, interleukin 1␤, interleukin 6, and platelet-derived growth factor-␣/␤), 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. Key Words: pulmonary hypertension Ⅲ resveratrol Ⅲ oxidative stress Ⅲ endothelial dysfunction Ⅲ inflammation P ulmonary hypertension is a syndrome that encompasses several diseases, all of which have in common increased pulmonary artery pressures. Idiopathic ("primary") pulmonary hypertension is a rare disease caused by genetic defects in the bone morphogenetic protein signaling pathways. Common causes of "secondary" forms of pulmonary hypertension include the following: (1) pulmonary hypertension associated with chronic obstructive pulmonary disease; (2) pulmonary embolism; and (3) pressure/volume overload-related pulmonary hypertension. In addition, pulmonary hypertension often develops in patients with autoimmune diseases or as a severe adverse effect of anorectic drug treatment. Despite the diverse etiologic differences, many similarities in the pathological alterations in pulmonary arteries occur among the various forms of pulmonary hypertension, ie, vascular remodeling, including cellular proliferation in both the intima and media; endothelial dysfunction/increased vasoconstriction; and activation of inflammatory processes (eg, inflammatory cytokine expression and monocyte infiltration).Current therapies for chronic pulmonary hypertension are designed to reduce pulmonary arterial resistance by inducing vasodilation (eg, NO inhalation, stimulation of cGMP production by phosphodiesterase inhibitors, endothelin receptor antagonists, and prostacyclin analogs). These therapeutic approaches mainly provide ...

Role of Oxidized Lipids in Pulmonary Arterial Hypertension

“…[94][95][96][97] Tissue hypoxia and an increase of inflammatory cytokines in the lungs of animal models of PH lead to elevated levels of ROSs. 58,97 PAH is associated with oxidative stress arising from the accumulation of ROSs, including superoxide and peroxide. Reaction of these highly reactive molecules with functional groups in membrane lipids and proteins can produce harmful oxidative-breakdown products.…”

Pulmonary Hypertension Is a Probable NO/ONOO−Cycle Disease: A Review

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“…Firstly, it is much more difficult, in general, to cure disease than to prevent it and this is to be especially expected for such a mechanism as the NO/ONOO − cycle, whose robust structure (Figures 1(a)-1(e)) strongly argues that it is difficult to down-regulate. ese studies were basically preventative rather than curative [304][305][306]. Furthermore, the activity of SIRT1 [314], which mediates each of these resveratrol effects, is sensitive to oxidative inactivation and is also dependent on NAD but NAD can be massively depleted by the elevation of PARP activity by ONOO − in the NO/ONOO − cycle (see number 18 of the 34 mechanisms).…”

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