TY - JOUR
T1 - Grape seed proanthocyanidins protect cardiomyocytes from ischemia and reperfusion injury via Akt-NOS signaling
AU - Shao, Zuo Hui
AU - Wojcik, Kimberly R.
AU - Dossumbekova, Anar
AU - Hsu, Chinwang
AU - Mehendale, Sangeeta R.
AU - Li, Chang Qing
AU - Qin, Yimin
AU - Sharp, Willard W.
AU - Chang, Wei Tien
AU - Hamann, Kimm J.
AU - Yuan, Chun Su
AU - Vanden Hoek, Terry L.
PY - 2009/7/1
Y1 - 2009/7/1
N2 - Ischemia/reperfusion (I/R) injury in cardiomyocytes is related to excess reactive oxygen species (ROS) generation and can be modulated by nitric oxide (NO). We have previously shown that grape seed proanthocyanidin extract (GSPE), a naturally occurring antioxidant, decreased ROS and may potentially stimulate NO production. In this study, we investigated whether GSPE administration at reperfusion was associated with cardioprotection and enhanced NO production in a cardiomyocyte I/R model. GSPE attenuated I/R-induced cell death [18.0 ± 1.8% (GSPE, 50 μg/ml) vs. 42.3 ± 3.0% (I/R control), P < 0.001], restored contractility (6/6 vs. 0/6, respectively), and increased NO release. The NO synthase (NOS) inhibitor Nω-nitro-L-arginine methyl ester (L-NAME, 200 μM) significantly reduced GSPE-induced NO release and its associated cardioprotection [32.7 ± 2.7% (GSPE + L-NAME) vs. 18.0 ± 1.8% (GSPE alone), P < 0.01]. To determine whether GSPE induced NO production was mediated by the Akt-eNOS pathway, we utilized the Akt inhibitor API-2. API-2 (10 μM) abrogated GSPE-induced protection [44.3% ± 2.2% (GSPE + API-2) vs. 27.0% ± 4.3% (GSPE alone), P < 0.01], attenuated the enhanced phosphorylation of Akt at Ser473 in GSPE-treated cells and attenuated GSPE-induced NO increases. Simultaneously blocking NOS activation (L-NAME) and Akt (API-2) resulted in decreased NO levels similar to using each inhibitor independently. These data suggest that in the context of GSPE stimulation, Akt may help activate eNOS, leading to protective levels of NO. GSPE offers an alternative approach to therapeutic cardioprotection against I/R injury and may offer unique opportunities to improve cardiovascular health by enhancing NO production and increasing Akt-eNOS signaling.
AB - Ischemia/reperfusion (I/R) injury in cardiomyocytes is related to excess reactive oxygen species (ROS) generation and can be modulated by nitric oxide (NO). We have previously shown that grape seed proanthocyanidin extract (GSPE), a naturally occurring antioxidant, decreased ROS and may potentially stimulate NO production. In this study, we investigated whether GSPE administration at reperfusion was associated with cardioprotection and enhanced NO production in a cardiomyocyte I/R model. GSPE attenuated I/R-induced cell death [18.0 ± 1.8% (GSPE, 50 μg/ml) vs. 42.3 ± 3.0% (I/R control), P < 0.001], restored contractility (6/6 vs. 0/6, respectively), and increased NO release. The NO synthase (NOS) inhibitor Nω-nitro-L-arginine methyl ester (L-NAME, 200 μM) significantly reduced GSPE-induced NO release and its associated cardioprotection [32.7 ± 2.7% (GSPE + L-NAME) vs. 18.0 ± 1.8% (GSPE alone), P < 0.01]. To determine whether GSPE induced NO production was mediated by the Akt-eNOS pathway, we utilized the Akt inhibitor API-2. API-2 (10 μM) abrogated GSPE-induced protection [44.3% ± 2.2% (GSPE + API-2) vs. 27.0% ± 4.3% (GSPE alone), P < 0.01], attenuated the enhanced phosphorylation of Akt at Ser473 in GSPE-treated cells and attenuated GSPE-induced NO increases. Simultaneously blocking NOS activation (L-NAME) and Akt (API-2) resulted in decreased NO levels similar to using each inhibitor independently. These data suggest that in the context of GSPE stimulation, Akt may help activate eNOS, leading to protective levels of NO. GSPE offers an alternative approach to therapeutic cardioprotection against I/R injury and may offer unique opportunities to improve cardiovascular health by enhancing NO production and increasing Akt-eNOS signaling.
KW - Akt
KW - Cardiomyocytes
KW - Grape seed proanthocyanidin extract
KW - Ischemia/reperfusion injury
KW - Nitric oxide
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U2 - 10.1002/jcb.22170
DO - 10.1002/jcb.22170
M3 - Article
C2 - 19388003
AN - SCOPUS:67650064637
SN - 0730-2312
VL - 107
SP - 697
EP - 705
JO - Journal of Cellular Biochemistry
JF - Journal of Cellular Biochemistry
IS - 4
ER -