Modulation of microRNA 20b with resveratrol and longevinex is linked with their potent anti‐angiogenic action in the ischaemic myocardium and synergestic effects of resveratrol and γ‐tocotrienol

Partha Mukhopadhyay,Hajime Otani,Md Kaimul Ahsan,Dipak K Das,Somak Das

doi:10.1111/j.1582-4934.2011.01480.x

Abstract

Resveratrol, a constituent of red wine, and γ-tocotrienol, a constituent of palm oil are important for cardioprotection. Although microRNAs are known regulators for genes involved in cardiac remodelling, the regulatory pathway involving microRNA has not been studied so far. We explored the cardioprotection by resveratrol, longevinex and γ−tocotrienol in ischaemia/reperfusion(I/R) model of rat and determined miRNA profile from isolated RNA. Systemic analyses of miRNA array and theirs targets were determined using a number of computational approaches. Resveratrol and γ-tocotrienol, either alone or in combination, modulated the expression pattern of miRNAs close to the control level based on PCA analyses. Differential expression was observed in over 75 miRNAs, some of them, such as miR-21 and miR-20b (anti-angiogenic) were previously implicated in cardiac remodelling. The target genes for the highest differentially expressed miRNA include genes of various molecular functions such as TGFβ1–Smad3 signalling pathway, inflammation and their transcription factors, which may play key role in reducing I/R injury. Administration of antagomiR-20 attenuated I/R induced vascular endothelial growth factor and HIF1α level. All the interventions treated for 3 weeks lead to significant cardioprotection against ischaemia/reperfusion injury. A unique signature of miRNA profile is observed in control heart pretreated with resveratrol or γ-tocotrienol. We have determined specific group of miRNA in heart that have altered during IR injuries. Most of those altered microRNA expressions modulated close to their basal level in resveratrol or longevinex treated I/R rat. Interestingly, resveratrol and γ-tocotrienol resulted in synergestic action.

Highlights

Human diet consists of a wide number of plant-derived polyphenolic compounds, which may protect against cardiovascularJ
RNAs were isolated after 30 min. ischaemia and 2-hr reperfusion of the heart from IR samples or from sham vehicle (BS) samples processed the same way without ischaemia and reperfusion
Western blot results showed that vascular endothelial growth factor (VEGF) and HIF-1␣ were down-regulated with any of the above treatment and antagomir 20b prevented the down-regulation of the values

Summary

Introduction

Human diet consists of a wide number of plant-derived polyphenolic compounds, which may protect against cardiovascularJ. Vol 16, No 10, 2012 pound ␥-tocotrienol, member of Vitamin E family, has been implicated in exerting beneficial effect in cardiovascular aging, diabetes and anti-angiogenesis [6,7,8] The most prominent way resveratrol functions is probably through its ability to perform intracellular signalling and alter gene expression. The most prominent mechanism appears to be its ability to induce several longevity genes including Sirt, Sirt, Sirt, FoxO1, Foxo3a and PBEF [5]. Resveratrol prevents agingrelated decline in cardiovascular function without affecting actual survival or life span of mice [5]. Resveratrol and ␥tocotrienol possess a myriad of beneficial effects and can act at multiple levels, such as cellular signalling, enzymatic pathways, apoptosis and gene expression

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Results

Conclusion