Abstract
Scutellarin (SCU), a flavonoid glycoside compound, has been successfully used in clinic for treatment of ischemic diseases in China. In this report, we checked the effects of SCU on endothelium dysfunction (ED) of coronary artery (CA) against myocardial ischemia reperfusion (MIR) injury in vivo. The involvement of PKG-Iα was further studied using cultured endothelial cells subjected to hypoxia reoxygenation (HR) injury in vitro. In rat MIR model, SCU (45 and 90 mg/kg, iv) significantly reduced ischemic size and restored the endothelium-dependent vasodilation of isolated CA rings. PKG inhibitor Rp-8-Br-cGMP (50 μg/kg, iv) could ameliorate the protective effects of SCU. Increase in phosphorylation of vasodilator-stimulated phosphoprotein (VASP), a main substrate of PKG, at Ser 239 was observed in both heart tissue and serum of SCU-treated animals. In cultured human cardiac microvascular endothelial cells (HCMECs), SCU (1 and 10 μM) dose-dependently protected cell viability and increased the mRNA and protein level of PKG-Iα against HR injury. The activity of PKG was also increased by SCU treatment. The activation of PKG–1α was then studied using targeted proteomic analysis (MRM-MS) checking the phosphorylation state of the autophosphorylation domain (aa42-94). Significant decrease in phosphorylation of PKG-Iα at Ser50, Ser72, Ser89 was induced by HR injury while SCU treatment significantly increased the phosphorylation of PKG-Iα, not only at Ser50, Ser72 and Ser89, but also at Ser44 and Thr58 (two novel phosphorylation domains). Our results demonstrate PKG-Iα might play an important role in the protective effects of SCU on ED against MIR injury.
Highlights
Scutellarin (SCU) is a flavonoid glycoside compound (4’, 5, 6-trihydroxy flavonoid-7-glucuronide) isolated from the traditional Chinese medicine plant Erigeron breviscapus (Vant.) Hand
As p-vasodilator-stimulated phosphoprotein (VASP) Ser239 is an indicator of PKG activation, the results suggested that activation of PKG was involved in the protective effects of SCU against myocardial ischemia reperfusion (MIR) injury
The present study demonstrated that SCU, a flavonoid glycoside successfully used in clinic in China for treatment of ischemic diseases, could protect endothelium function against MIR injury in vivo
Summary
Scutellarin (SCU) is a flavonoid glycoside compound (4’, 5, 6-trihydroxy flavonoid-7-glucuronide) isolated from the traditional Chinese medicine plant Erigeron breviscapus (Vant.) Hand. SCU was found to induce endothelium-dependent vasodilative effect partially affected by inhibitors of NOS and guanylate cyclase in isolated mouse aorta [21]. We focused on investigating whether SCU have direct cytoprotective effects on endothelial cells against IR injury. After finding PKG–1α as a possible target of SCU, the phosphorylation state of PKG–1α was further studied because phosphorylation played an important role in PKG-I activation [22,23,24,25]. The phosphorylation states of PKG-Iα under different treatments were analyzed in the present study using MRM-MS, a targeted proteomic analysis method, to clarify the PKG-Iα function in IR injury and the protective mechanism of SCU
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