Phenolic glucoside gastrodin (Gas), which is a main component extracted from the Chinese herbs Gastrodia elata Bl, is a well-known natural calcium antagonist with antioxidant and anti-inflammatory functions. It has long been used clinically for treatment of cardiovascular and cerebrovascular diseases. Previous studies have shown that gastrodin possesses comprehensive pharmacological functions. However, very little is known about whether gastrodin has protective role on cardiac hypertrophy. The aim of this study was to determine whether gastrodin attenuates pressure overload-induced cardiac hypertrophy in mice and to clarify the underlying molecular mechanisms. Our data demonstrated that gastrodin prevented cardiac hypertrophy induced by aortic banding (AB), as assessed by heart weight/body weight and lung weight/body weight ratios, echocardiographic parameters, and gene expression of hypertrophic markers. The inhibitory effect of gastrodin on cardiac hypertrophy is mediated by ERK1/2 signaling and GATA-4 activation. Further studies showed that gastrodin attenuated fibrosis and collagen synthesis through abrogating ERK1/2 signaling pathway. Therefore, these findings indicated that gastrodin, which is a potentially safe and inexpensive therapy for clinical use, has protective potential in targeting cardiac hypertrophy and fibrosis through suppression of ERK1/2 signaling.

The proliferation of pulmonary artery smooth muscle cells (PASMCs) contributes to the development of pulmonary vascular remodeling, ultimately leading to pulmonary hypertension. In this study, the effects and molecular mechanisms of salidroside on the platelet‑derived growth factor (PDGF)‑BB‑induced proliferation of primary cultured rat PASMCs were investigated. The presented data demonstrated that salidroside significantly inhibited the proliferation and DNA synthesis of PASMCs induced by PDGF‑BB in a dose‑ and time‑dependent manner, without cell cytotoxicity. In accordance with these findings, salidroside blocked progression through G0/G1 to S phase of the cell cycle. The salidroside‑induced inhibition of the cell cycle was associated with the inhibition of cyclin D1, cyclin E, cyclin‑dependent kinase 2 (CDK2) and CDK4 mRNA expression, as well as an increase in the mRNA expression of p27 in PDGF‑BB‑stimulated PASMCs. Further experiments showed that the beneficial effect of salidroside on blocking the proliferation of PASMCs was associated with the suppression of the AKT/glycogen synthase kinase 3 β (GSK3β) signaling pathway, but did not involve the extracellular signal‑regulated kinase 1/2, p38 and c‑Jun‑N‑terminal kinase signaling pathways. These results indicate that salidroside suppresses PDGF‑BB‑induced PASMC proliferation through the AKT/GSK3β signaling pathway and suggests that it may be a feasible therapy for pulmonary vascular remodeling diseases.

Abnormal proliferation, migration, and phenotypic modulation of vascular smooth muscle cells (VSMCs) are critical factors in neointima formation during restenosis. The purpose of this study is to determine the efficacy and possible cell signaling mechanisms of apigenin in VSMC activation induced by platelet-derived growth factor (PDGF)-BB and injury-induced neointima formation. Our data revealed a dose-dependent apigenin inhibition of PDGF-BB-induced proliferation of VSMCs by arresting cells in G0/G1-phase of the cell cycle as determined using 5-bromo-2'-deoxyuridine incorporation and flow cytometry. This was associated with the inhibition of cyclin-dependent kinase (CDK) 4,6 expression and an increase in p27Kip1 levels in PDGF-stimulated VSMCs. Moreover, apigenin was also found to regulate PDGF-induced migration and expression of smooth-muscle-specific contractile markers. Mechanistically, the PDGF-BB-induced phosphorylation of PDGF-receptor β (PDGF-Rβ), Akt/glycogen synthase kinase(GSK)3β, extracellular signal-regulated kinase1/2 (ERK1/2), and signal transducers and activators of transcription 3 (STAT3) is negatively modulated by apigenin. For the in vivo studies using a mouse carotid arterial injury model, the administration of apigenin resulted in a significant inhibition of the neointima/media ratio and proliferating cell nuclear antigen (PCNA)-positive cells. These results demonstrate that apigenin can suppress PDGF-induced VSMC activation and neointima hyperplasia after vascular injury; these beneficial effects are probably the result of the blockade of PDGF-Rβ phosphorylation and its downstream signal transduction, including the Akt/GSK-3β, ERK1/2, and STAT3 pathways. The results suggest that apigenin may be a potential therapeutic candidate for the prevention of restenosis.