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Astragalus polysaccharide suppresses doxorubicin-induced cardiotoxicity by regulating the PI3k/Akt and p38MAPK pathways.

Cao Y, Ruan Y, Shen T, Huang X, Li M, Yu W, Zhu Y, Man Y, Wang S, Li J - Oxid Med Cell Longev (2014)

Bottom Line: Astragalus polysaccharide (APS), the extract of Astragalus membranaceus with strong antitumor and antiglomerulonephritis activity, can effectively alleviate inflammation.Treatment of patients with the chemotherapeutic drug doxorubicin led to heart dysfunction.In addition, there was profound inhibition of p38MAPK and activation of Akt after APS treatment.

View Article: PubMed Central - PubMed

Affiliation: The Fifth Clinical Hospital of Peking University, Health Science Center, Beijing 100730, China ; Key Laboratory of Geriatrics, Beijing Hospital, Beijing Institute of Geriatrics, Ministry of Health of China, Beijing 100730, China.

ABSTRACT

Background: Doxorubicin, a potent chemotherapeutic agent, is associated with acute and chronic cardiotoxicity, which is cumulatively dose-dependent. Astragalus polysaccharide (APS), the extract of Astragalus membranaceus with strong antitumor and antiglomerulonephritis activity, can effectively alleviate inflammation. However, whether APS could ameliorate chemotherapy-induced cardiotoxicity is not understood. Here, we investigated the protective effects of APS on doxorubicin-induced cardiotoxicity and elucidated the underlying mechanisms of the protective effects of APS.

Methods: We analyzed myocardial injury in cancer patients who underwent doxorubicin chemotherapy and generated a doxorubicin-induced neonatal rat cardiomyocyte injury model and a mouse heart failure model. Echocardiography, reactive oxygen species (ROS) production, TUNEL, DNA laddering, and Western blotting were performed to observe cell survival, oxidative stress, and inflammatory signal pathways in cardiomyocytes.

Results: Treatment of patients with the chemotherapeutic drug doxorubicin led to heart dysfunction. Doxorubicin reduced cardiomyocyte viability and induced C57BL/6J mouse heart failure with concurrent elevated ROS generation and apoptosis, which, however, was attenuated by APS treatment. In addition, there was profound inhibition of p38MAPK and activation of Akt after APS treatment.

Conclusions: These results demonstrate that APS could suppress oxidative stress and apoptosis, ameliorating doxorubicin-mediated cardiotoxicity by regulating the PI3k/Akt and p38MAPK pathways.

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Related in: MedlinePlus

APS attenuates doxorubicin-induced heart injury by regulating p38MAPK and Akt phosphorylation. (a) APS decreases p38MAPK phosphorylation in a concentration-dependent manner in NRVMs as assayed by Western blotting (n = 3, ###P < 0.001 versus control group, **P < 0.01 versus the doxorubicin-treated group, and ***P < 0.001 versus the doxorubicin-treated group). (b) APS increases Akt phosphorylation in NRVMs (n = 3, ##P < 0.01 versus control group, **P < 0.01 versus the doxorubicin-treated group). (c) Western blotting and average data for p38MAPK and Akt phosphorylation in sham and doxorubicin-induced heart injury mice and mice pretreated with APS (n = 8-9, ***P < 0.001). (d) Time course of doxorubicin-induced Akt phosphorylation in NRVMs (n = 3, *P < 0.05 versus 0 hr sample, **P < 0.01 versus 0 hr sample). (e) The APS protective effect was reversed by the PI3K inhibitor LY294002. NRVMs were pretreated for 1 h with 2 μM LY294002 prior to APS (50 μg/mL) and DOX (1 μM) treatment. Akt phosphorylation and cleaved caspase 3 were analyzed by Western blotting (n = 3, *P < 0.05, **P < 0.01). (f) Cardiomyocyte apoptosis as detected by DNA laddering in control and DOX-treated NRVMs, NRVMs pretreated with APS (50 μg/mL) followed by DOX treatment, and NRVMs pretreated with APS (50 μg/mL) and LY294002 (2 μM) followed by DOX treatment (n = 4).
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fig5: APS attenuates doxorubicin-induced heart injury by regulating p38MAPK and Akt phosphorylation. (a) APS decreases p38MAPK phosphorylation in a concentration-dependent manner in NRVMs as assayed by Western blotting (n = 3, ###P < 0.001 versus control group, **P < 0.01 versus the doxorubicin-treated group, and ***P < 0.001 versus the doxorubicin-treated group). (b) APS increases Akt phosphorylation in NRVMs (n = 3, ##P < 0.01 versus control group, **P < 0.01 versus the doxorubicin-treated group). (c) Western blotting and average data for p38MAPK and Akt phosphorylation in sham and doxorubicin-induced heart injury mice and mice pretreated with APS (n = 8-9, ***P < 0.001). (d) Time course of doxorubicin-induced Akt phosphorylation in NRVMs (n = 3, *P < 0.05 versus 0 hr sample, **P < 0.01 versus 0 hr sample). (e) The APS protective effect was reversed by the PI3K inhibitor LY294002. NRVMs were pretreated for 1 h with 2 μM LY294002 prior to APS (50 μg/mL) and DOX (1 μM) treatment. Akt phosphorylation and cleaved caspase 3 were analyzed by Western blotting (n = 3, *P < 0.05, **P < 0.01). (f) Cardiomyocyte apoptosis as detected by DNA laddering in control and DOX-treated NRVMs, NRVMs pretreated with APS (50 μg/mL) followed by DOX treatment, and NRVMs pretreated with APS (50 μg/mL) and LY294002 (2 μM) followed by DOX treatment (n = 4).

Mentions: To further elucidate the underlying mechanisms responsible for the protective effects of APS on doxorubicin-induced heart injury, we analyzed changes in several important cell survival and death signaling pathways including the PI3K/Akt, ERK, p38MAPK, and JNK pathways in response to doxorubicin treatment and APS pretreatment. We found that pretreatment with APS significantly attenuates doxorubicin-induced p38MAPK phosphorylation in a concentration-dependent manner in NRVMs (Figure 5(a)). However, the ERK and JNK signaling pathways were not responsive to doxorubicin treatment and APS pretreatment (data not shown). Moreover, doxorubicin treatment increased the Akt phosphorylation in NRVMs, which was further increased by APS pretreatment (Figure 5(b)). After pretreatment with APS, in vivo Akt phosphorylation was dramatically enhanced, which corresponded with the results obtained in NRVMs. However, the Akt phosphorylation found with doxorubicin-induced mouse heart failure significantly decreased (Figure 5(c)).


Astragalus polysaccharide suppresses doxorubicin-induced cardiotoxicity by regulating the PI3k/Akt and p38MAPK pathways.

Cao Y, Ruan Y, Shen T, Huang X, Li M, Yu W, Zhu Y, Man Y, Wang S, Li J - Oxid Med Cell Longev (2014)

APS attenuates doxorubicin-induced heart injury by regulating p38MAPK and Akt phosphorylation. (a) APS decreases p38MAPK phosphorylation in a concentration-dependent manner in NRVMs as assayed by Western blotting (n = 3, ###P < 0.001 versus control group, **P < 0.01 versus the doxorubicin-treated group, and ***P < 0.001 versus the doxorubicin-treated group). (b) APS increases Akt phosphorylation in NRVMs (n = 3, ##P < 0.01 versus control group, **P < 0.01 versus the doxorubicin-treated group). (c) Western blotting and average data for p38MAPK and Akt phosphorylation in sham and doxorubicin-induced heart injury mice and mice pretreated with APS (n = 8-9, ***P < 0.001). (d) Time course of doxorubicin-induced Akt phosphorylation in NRVMs (n = 3, *P < 0.05 versus 0 hr sample, **P < 0.01 versus 0 hr sample). (e) The APS protective effect was reversed by the PI3K inhibitor LY294002. NRVMs were pretreated for 1 h with 2 μM LY294002 prior to APS (50 μg/mL) and DOX (1 μM) treatment. Akt phosphorylation and cleaved caspase 3 were analyzed by Western blotting (n = 3, *P < 0.05, **P < 0.01). (f) Cardiomyocyte apoptosis as detected by DNA laddering in control and DOX-treated NRVMs, NRVMs pretreated with APS (50 μg/mL) followed by DOX treatment, and NRVMs pretreated with APS (50 μg/mL) and LY294002 (2 μM) followed by DOX treatment (n = 4).
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fig5: APS attenuates doxorubicin-induced heart injury by regulating p38MAPK and Akt phosphorylation. (a) APS decreases p38MAPK phosphorylation in a concentration-dependent manner in NRVMs as assayed by Western blotting (n = 3, ###P < 0.001 versus control group, **P < 0.01 versus the doxorubicin-treated group, and ***P < 0.001 versus the doxorubicin-treated group). (b) APS increases Akt phosphorylation in NRVMs (n = 3, ##P < 0.01 versus control group, **P < 0.01 versus the doxorubicin-treated group). (c) Western blotting and average data for p38MAPK and Akt phosphorylation in sham and doxorubicin-induced heart injury mice and mice pretreated with APS (n = 8-9, ***P < 0.001). (d) Time course of doxorubicin-induced Akt phosphorylation in NRVMs (n = 3, *P < 0.05 versus 0 hr sample, **P < 0.01 versus 0 hr sample). (e) The APS protective effect was reversed by the PI3K inhibitor LY294002. NRVMs were pretreated for 1 h with 2 μM LY294002 prior to APS (50 μg/mL) and DOX (1 μM) treatment. Akt phosphorylation and cleaved caspase 3 were analyzed by Western blotting (n = 3, *P < 0.05, **P < 0.01). (f) Cardiomyocyte apoptosis as detected by DNA laddering in control and DOX-treated NRVMs, NRVMs pretreated with APS (50 μg/mL) followed by DOX treatment, and NRVMs pretreated with APS (50 μg/mL) and LY294002 (2 μM) followed by DOX treatment (n = 4).
Mentions: To further elucidate the underlying mechanisms responsible for the protective effects of APS on doxorubicin-induced heart injury, we analyzed changes in several important cell survival and death signaling pathways including the PI3K/Akt, ERK, p38MAPK, and JNK pathways in response to doxorubicin treatment and APS pretreatment. We found that pretreatment with APS significantly attenuates doxorubicin-induced p38MAPK phosphorylation in a concentration-dependent manner in NRVMs (Figure 5(a)). However, the ERK and JNK signaling pathways were not responsive to doxorubicin treatment and APS pretreatment (data not shown). Moreover, doxorubicin treatment increased the Akt phosphorylation in NRVMs, which was further increased by APS pretreatment (Figure 5(b)). After pretreatment with APS, in vivo Akt phosphorylation was dramatically enhanced, which corresponded with the results obtained in NRVMs. However, the Akt phosphorylation found with doxorubicin-induced mouse heart failure significantly decreased (Figure 5(c)).

Bottom Line: Astragalus polysaccharide (APS), the extract of Astragalus membranaceus with strong antitumor and antiglomerulonephritis activity, can effectively alleviate inflammation.Treatment of patients with the chemotherapeutic drug doxorubicin led to heart dysfunction.In addition, there was profound inhibition of p38MAPK and activation of Akt after APS treatment.

View Article: PubMed Central - PubMed

Affiliation: The Fifth Clinical Hospital of Peking University, Health Science Center, Beijing 100730, China ; Key Laboratory of Geriatrics, Beijing Hospital, Beijing Institute of Geriatrics, Ministry of Health of China, Beijing 100730, China.

ABSTRACT

Background: Doxorubicin, a potent chemotherapeutic agent, is associated with acute and chronic cardiotoxicity, which is cumulatively dose-dependent. Astragalus polysaccharide (APS), the extract of Astragalus membranaceus with strong antitumor and antiglomerulonephritis activity, can effectively alleviate inflammation. However, whether APS could ameliorate chemotherapy-induced cardiotoxicity is not understood. Here, we investigated the protective effects of APS on doxorubicin-induced cardiotoxicity and elucidated the underlying mechanisms of the protective effects of APS.

Methods: We analyzed myocardial injury in cancer patients who underwent doxorubicin chemotherapy and generated a doxorubicin-induced neonatal rat cardiomyocyte injury model and a mouse heart failure model. Echocardiography, reactive oxygen species (ROS) production, TUNEL, DNA laddering, and Western blotting were performed to observe cell survival, oxidative stress, and inflammatory signal pathways in cardiomyocytes.

Results: Treatment of patients with the chemotherapeutic drug doxorubicin led to heart dysfunction. Doxorubicin reduced cardiomyocyte viability and induced C57BL/6J mouse heart failure with concurrent elevated ROS generation and apoptosis, which, however, was attenuated by APS treatment. In addition, there was profound inhibition of p38MAPK and activation of Akt after APS treatment.

Conclusions: These results demonstrate that APS could suppress oxidative stress and apoptosis, ameliorating doxorubicin-mediated cardiotoxicity by regulating the PI3k/Akt and p38MAPK pathways.

Show MeSH
Related in: MedlinePlus