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Effectiveness of Panax ginseng on Acute Myocardial Ischemia Reperfusion Injury Was Abolished by Flutamide via Endogenous Testosterone-Mediated Akt Pathway.

Pei L, Shaozhen H, Gengting D, Tingbo C, Liang L, Hua Z - Evid Based Complement Alternat Med (2013)

Bottom Line: RSE (80 mg/kg) significantly inhibited myocardial infarction and CK and LDH activities, while coadministration of flutamide abolished this effect of RSE.Western blot analysis showed that RSE significantly reversed the decreases of expression and activation of PI3K, Akt, and eNOS evoked by ischemia, whereas flutamide attenuated the effects of these protective mechanisms induced by RSE.Our results for the first time indicate that blocking androgen receptor abolishes the ability of Panax ginseng to protect the heart from myocardial I/R injury.

View Article: PubMed Central - PubMed

Affiliation: State Key Laboratory for Quality Research of Chinese Medicine, Macau University of Science and Technology, Avenida Wai Long, Taipa, Macau, China.

ABSTRACT
Mechanisms for Panax ginseng's cardioprotective effect against ischemia reperfusion injury involve the estrogen-mediated pathway, but little is known about the role of androgen. A standardized Panax ginseng extract (RSE) was orally given with or without flutamide in a left anterior descending coronary artery ligation rat model. Infarct size, CK and LDH activities were measured. Time-related changes of NO, PI3K/Akt/eNOS signaling, and testosterone concentration were also investigated. RSE (80 mg/kg) significantly inhibited myocardial infarction and CK and LDH activities, while coadministration of flutamide abolished this effect of RSE. NO was increased by RSE and reached a peak after 15 min of ischemia; however, flutamide cotreatment suppressed this elevation. Western blot analysis showed that RSE significantly reversed the decreases of expression and activation of PI3K, Akt, and eNOS evoked by ischemia, whereas flutamide attenuated the effects of these protective mechanisms induced by RSE. RSE completely reversed the dropping of endogenous testosterone level induced by I/R injury. Flutamide plus RSE treatment not only abolished RSE's effect but also produced a dramatic change on endogenous testosterone level after pretreatment and ischemia. Our results for the first time indicate that blocking androgen receptor abolishes the ability of Panax ginseng to protect the heart from myocardial I/R injury.

No MeSH data available.


Related in: MedlinePlus

Effects of RSE and flutamide on time course changes of activation and expression of PI3K/Akt/eNOS signaling. PI3K/Akt/eNOS signaling in heart was investigated by Western blot at six time points. The blot was reprobed sequentially with antibodies special for PI3K or phospho-PI3K (Tyr458), Akt or phospho-Akt (Ser473), or eNOS or phospho-eNOS (Ser1177). Identical results were obtained in three separate rat hearts at each time point. Normalization of Western blot was ensured by GAPDH.
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fig6: Effects of RSE and flutamide on time course changes of activation and expression of PI3K/Akt/eNOS signaling. PI3K/Akt/eNOS signaling in heart was investigated by Western blot at six time points. The blot was reprobed sequentially with antibodies special for PI3K or phospho-PI3K (Tyr458), Akt or phospho-Akt (Ser473), or eNOS or phospho-eNOS (Ser1177). Identical results were obtained in three separate rat hearts at each time point. Normalization of Western blot was ensured by GAPDH.

Mentions: Since the NO production during I/R injury is closely regulated by the PI3K/AKT/eNOS signaling pathway, we further investigated the influence of RSE with or without joint administration of flutamide on this pathway during pretreatment and I/R period. Figure 6 illustrates representative results of the effects of RSE and flutamide on expression and activation of PI3K/Akt/eNOS pathway at the different time points during pretreatment and I/R period. Total and active PI3K, Akt, and eNOS were approximately equivalent in the sham group throughout the pretreatment and I/R periods. I/R significantly suppressed the expression and activation of PI3K after 30 min ischemia (Figures 6(a) and 6(b)). Expression of Akt in the IRI group was reduced slightly after ischemia, while its activation (p-Akt) was dramatically inhibited after ischemia (Figures 6(c) and 6(d)). Total eNOS in IRI group was decreased after ischemia and gradually returned to normal levels after reperfusion. However, the p-eNOS was constantly decreased compared with the sham group (Figures 6(e) and 6(f)). RSE pretreatment returned PI3K back to a normal level and further upregulated activation of PI3K during the 30 min ischemia period. Although RSE did not significantly change the total form of Akt, it significantly elevated the p-Akt at 90 min after reperfusion. Meanwhile, in the presence of RSE pretreatment, active and total eNOS decreased remarkably at 15 min after ischemia and returned to normal level at 90 min after reperfusion. In the RSE and flutamide joint administration group, p-Akt dramatically and continuously decreased at 30 min after pretreatment. Interestingly, the expression and activation of eNOS in myocardial tissue was significantly reduced at 30 min after pretreatment. Combined with flutamide, RSE pretreatment did not show any obvious influence on returning total or active form of eNOS to normal levels during the I/R period. These results strongly suggest that the anti-ischemia reperfusion injury effect of RSE might result from, or at least involves, PI3K/Akt-activated eNOS activation in the early phase of ischemia (15 min after ischemia). This result is also partly in accordance with the results of NO production assay.


Effectiveness of Panax ginseng on Acute Myocardial Ischemia Reperfusion Injury Was Abolished by Flutamide via Endogenous Testosterone-Mediated Akt Pathway.

Pei L, Shaozhen H, Gengting D, Tingbo C, Liang L, Hua Z - Evid Based Complement Alternat Med (2013)

Effects of RSE and flutamide on time course changes of activation and expression of PI3K/Akt/eNOS signaling. PI3K/Akt/eNOS signaling in heart was investigated by Western blot at six time points. The blot was reprobed sequentially with antibodies special for PI3K or phospho-PI3K (Tyr458), Akt or phospho-Akt (Ser473), or eNOS or phospho-eNOS (Ser1177). Identical results were obtained in three separate rat hearts at each time point. Normalization of Western blot was ensured by GAPDH.
© Copyright Policy - open-access
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3824556&req=5

fig6: Effects of RSE and flutamide on time course changes of activation and expression of PI3K/Akt/eNOS signaling. PI3K/Akt/eNOS signaling in heart was investigated by Western blot at six time points. The blot was reprobed sequentially with antibodies special for PI3K or phospho-PI3K (Tyr458), Akt or phospho-Akt (Ser473), or eNOS or phospho-eNOS (Ser1177). Identical results were obtained in three separate rat hearts at each time point. Normalization of Western blot was ensured by GAPDH.
Mentions: Since the NO production during I/R injury is closely regulated by the PI3K/AKT/eNOS signaling pathway, we further investigated the influence of RSE with or without joint administration of flutamide on this pathway during pretreatment and I/R period. Figure 6 illustrates representative results of the effects of RSE and flutamide on expression and activation of PI3K/Akt/eNOS pathway at the different time points during pretreatment and I/R period. Total and active PI3K, Akt, and eNOS were approximately equivalent in the sham group throughout the pretreatment and I/R periods. I/R significantly suppressed the expression and activation of PI3K after 30 min ischemia (Figures 6(a) and 6(b)). Expression of Akt in the IRI group was reduced slightly after ischemia, while its activation (p-Akt) was dramatically inhibited after ischemia (Figures 6(c) and 6(d)). Total eNOS in IRI group was decreased after ischemia and gradually returned to normal levels after reperfusion. However, the p-eNOS was constantly decreased compared with the sham group (Figures 6(e) and 6(f)). RSE pretreatment returned PI3K back to a normal level and further upregulated activation of PI3K during the 30 min ischemia period. Although RSE did not significantly change the total form of Akt, it significantly elevated the p-Akt at 90 min after reperfusion. Meanwhile, in the presence of RSE pretreatment, active and total eNOS decreased remarkably at 15 min after ischemia and returned to normal level at 90 min after reperfusion. In the RSE and flutamide joint administration group, p-Akt dramatically and continuously decreased at 30 min after pretreatment. Interestingly, the expression and activation of eNOS in myocardial tissue was significantly reduced at 30 min after pretreatment. Combined with flutamide, RSE pretreatment did not show any obvious influence on returning total or active form of eNOS to normal levels during the I/R period. These results strongly suggest that the anti-ischemia reperfusion injury effect of RSE might result from, or at least involves, PI3K/Akt-activated eNOS activation in the early phase of ischemia (15 min after ischemia). This result is also partly in accordance with the results of NO production assay.

Bottom Line: RSE (80 mg/kg) significantly inhibited myocardial infarction and CK and LDH activities, while coadministration of flutamide abolished this effect of RSE.Western blot analysis showed that RSE significantly reversed the decreases of expression and activation of PI3K, Akt, and eNOS evoked by ischemia, whereas flutamide attenuated the effects of these protective mechanisms induced by RSE.Our results for the first time indicate that blocking androgen receptor abolishes the ability of Panax ginseng to protect the heart from myocardial I/R injury.

View Article: PubMed Central - PubMed

Affiliation: State Key Laboratory for Quality Research of Chinese Medicine, Macau University of Science and Technology, Avenida Wai Long, Taipa, Macau, China.

ABSTRACT
Mechanisms for Panax ginseng's cardioprotective effect against ischemia reperfusion injury involve the estrogen-mediated pathway, but little is known about the role of androgen. A standardized Panax ginseng extract (RSE) was orally given with or without flutamide in a left anterior descending coronary artery ligation rat model. Infarct size, CK and LDH activities were measured. Time-related changes of NO, PI3K/Akt/eNOS signaling, and testosterone concentration were also investigated. RSE (80 mg/kg) significantly inhibited myocardial infarction and CK and LDH activities, while coadministration of flutamide abolished this effect of RSE. NO was increased by RSE and reached a peak after 15 min of ischemia; however, flutamide cotreatment suppressed this elevation. Western blot analysis showed that RSE significantly reversed the decreases of expression and activation of PI3K, Akt, and eNOS evoked by ischemia, whereas flutamide attenuated the effects of these protective mechanisms induced by RSE. RSE completely reversed the dropping of endogenous testosterone level induced by I/R injury. Flutamide plus RSE treatment not only abolished RSE's effect but also produced a dramatic change on endogenous testosterone level after pretreatment and ischemia. Our results for the first time indicate that blocking androgen receptor abolishes the ability of Panax ginseng to protect the heart from myocardial I/R injury.

No MeSH data available.


Related in: MedlinePlus