Resveratrol reverses monocrotaline-induced pulmonary vascular and cardiac dysfunction: A potential role for atrogin-1 in smooth muscle

Abstract

Arterial remodeling contributes to the 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.

Resveratrol Protects Against Pulmonary Arterial Hypertension in Rats via Activation of Silent Information Regulator 1

“…Currently, several studies have documented that Rev possesses various biological properties, including antioxidant, anti-inflammatory, and anti-proliferative properties, and promotes cell differentiation and apoptosis [27-30]. The data from a recent study showed that Rev reversed the remodelling of the pulmonary vasculature by restoring atrophic gene expression in MCT-induced PH [18]. In addition, Zhou et al showed that Rev could elevate the activation of SIRT1 and p21 but decreased cyclin D1 expression in MCT-induced PAH [19].…”

“…Resveratrol (Rev, 3,5,4-trihydroxystilbene), a polyphenol isolated from grapes and polygonum cuspidatum, has been shown to possess antioxidative properties [17]. A recent study showed that Rev could reverse monocrotaline-induced pulmonary vascular remodelling and prevent the progression of PAH [18, 19]. However, the exact anti-PAH function of Rev has not been fully uncovered until now.…”

Monocrotaline-Induced Pulmonary Hypertension Involves Downregulation of Antiaging Protein Klotho and eNOS Activity

“…Recently, SIRT1 has come to the attention of researchers in the field, as it may protect against lung inflammation and PASMC proliferation. 46–48 Resveratrol, a SIRT1 activator, has been shown to prevent or rescue MCT-induced PAH in rats by reducing inflammation and oxidative stress and inhibiting PASMC proliferation. 46–48 Inhibition of SIRT1 increased SMC proliferation 48 , while resveratrol prevented SMC proliferation.…”

Preclinical and clinical evidence for the role of resveratrol in the treatment of cardiovascular diseases

“…In this model, resveratrol improved endothelial function, attenuated inflammation and oxidative stress, and inhibited proliferation of pulmonary artery smooth muscle cells [70]. In addition, resveratrol has also been shown to reverse established pulmonary hypertension when it was administered 28 days after the monocrotaline injection [71,72]. In a model of pulmonary thromboembolisminduced pulmonary hypertension, two doses of resveratrol (10 mg/kg; IP) significantly reduced mean pulmonary artery pressure through down-regulation of monocyte chemo-attractant protein-1 (MCP-1), and P-p38 mitogen-activated protein kinase (MAPK) [73].…”