Evaluation of resveratrol and tocotrienols as potential redox active compounds for cardioprotection

Dátum
2007-07-19T12:10:35Z
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Das, Samarjit
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Out of at least 8000 polyphenols, I have chosen resveratrol, and tocotrienols. My focus of study will be to find out the cardioprotective effect as well as the mechanism of these compounds. Resveratrol (3,4',5-Trihydroxy-trans-stilbene), a naturally occurring phytoalexin is found abundantly in grapes particularly in skin and seeds and in wines. Various recent studies have shown the cardioprotective effect of resveratrol is affected by the activation of the constitutive expression of NO. To find out whether cardioprotection by resveratrol is only through the release of NO or some other factors are also involved, I focused on Adenosine, which is a potent intermediate of myocardial preservation. Rats were assigned into i) control group; ii) KHB containing 10 µM resveratrol; iii) 10 µM resveratrol + 1 µM MRS 1191; iv) 10 µM resveratrol + 3 µM LY 294002; v) 10 µM resveratrol + 20 µM PD098059 vi) 10 µM resveratrol + 20 µM 098059 + 3 µM LY 294002; vii) 10 µM resveratrol + 10 µM SB 202190; or viii) 10 µM resveratrol + 1 µM H-89. All hearts were then subjected to 30 min ischemia followed by 2 h reperfusion. Control experiments were performed with vehicle (DMSO) only, MRS 1191 only, LY 294002 only or PD 098059 only or SB 202190 only or H 89 only. The results indicate that resveratrol preconditions the hearts through adenosine A3 receptor signaling that triggers the phosphorylation of CREB through both Akt-dependent and –independent pathways leading to cardioprotection. The most important finding of my study is that resveratrol increased the phosphorylation of what by ERK1/2 and p38 MAPK, which in turn phosphorylated MSK-1 leading to the activation of CREB, suggesting that phosphorylation of MSK-1 and subsequent activation of CREB, occurred via both p38MAPK ERK1/2. Resveratrol also increased the phosphorylation of MAPKAP kinase 2, the downstream target of p38MAP kinase. In agreement with these results, cardioprotective abilities of resveratrol were partially abolished either with an ERK1/2 inhibitor, PD 098,059 or with a p38 inhibitor, SB202190 and almost completely with a MSK-1 blocker, H-89. Tocotrienols, α, β, γ and δ are members of the vitamin E family. I chose to work with palm oil derived tocotrienols (TRF), in which the ratio of tocotrienols and tocopherols are 80 : 20. Cardioprotective effect of tocotrienols are not discover yet. Isolated rat hearts were perfused for 15 min with KHB buffer in the absence or presence of (0.035%) of TRF, presence of a cSrc inhibitor, PPI and the combination of TRF and PP1 as a next group. The hearts were then subjected to 30 min of global ischemia followed by 2 h of reperfusion. TRF was found to provide cardioprotection as evidenced by reduction of ischemia/reperfusion-mediated increase in ventricular dysfunction, ventricular arrhythmias and myocardial infarct size. Ischemia/reperfusion also upregulated cSrc expression and its phosphorylation. While TRF only minimally affected cSrc expression, it significantly inhibited the phosphorylation of cSrc. Tocotrienol was found to stabilize proteasome by preventing the ischemia/reperfusion-mediated reduction of 26S and 20S proteasomes. In contrast, PPI exerted a cardioprotective effect that is not mediated by the proteasome but rather through direct inhibition of cSrc. The results of this study showed for the first time that beneficial effects of tocotrienol are due to its ability to reduce cSrc activation that is linked with the stabilization of proteasomes.
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