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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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APS ameliorates doxorubicin-induced cardiotoxicity and apoptosis in vivo. (a) H&E staining of normal mice (Con) and mice with doxorubicin-induced heart failure (HF) (n = 5). (b) Representative TUNEL staining of apoptotic cells in normal and doxorubicin-induced heart injury samples. Red staining indicates TUNEL-positive cells (n = 5, *P < 0.05, **P < 0.01). (c) Western blotting and average data for caspase 3, caspase 9, and Bcl2 in sham, doxorubicin-induced heart injury mice (DOX), and mice with APS pretreatment followed by doxorubicin treatment (APS + DOX) (n = 15, **P < 0.01, ***P < 0.001). (d) Mouse heart function 5 days after doxorubicin injection as shown by fractional shortening % (FS %) and ejection fraction % (EF %) (n = 8, *P < 0.05, **P < 0.01).
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fig4: APS ameliorates doxorubicin-induced cardiotoxicity and apoptosis in vivo. (a) H&E staining of normal mice (Con) and mice with doxorubicin-induced heart failure (HF) (n = 5). (b) Representative TUNEL staining of apoptotic cells in normal and doxorubicin-induced heart injury samples. Red staining indicates TUNEL-positive cells (n = 5, *P < 0.05, **P < 0.01). (c) Western blotting and average data for caspase 3, caspase 9, and Bcl2 in sham, doxorubicin-induced heart injury mice (DOX), and mice with APS pretreatment followed by doxorubicin treatment (APS + DOX) (n = 15, **P < 0.01, ***P < 0.001). (d) Mouse heart function 5 days after doxorubicin injection as shown by fractional shortening % (FS %) and ejection fraction % (EF %) (n = 8, *P < 0.05, **P < 0.01).

Mentions: To determine whether APS could preserve heart function in vivo, we next generated a heart failure model using doxorubicin-treated C57BL/6 mice. As shown by H&E staining, doxorubicin-induced heart failure was associated with decreased thickening of the left ventricular wall and ventricular dilation (Figure 4(a)). The number of apoptotic cells was dramatically higher in hearts of doxorubicin-treated C57BL/6 mice (26.44 ± 7.72%) compared with hearts from control mice (2.55 ± 0.65%) as demonstrated by TUNEL staining. Importantly, pretreatment with APS attenuated doxorubicin-induced cardiomyocyte apoptosis (15.54 ± 6.06%) (Figure 4(b)). Moreover, Western blot analysis revealed that APS suppressed doxorubicin-induced caspase 3 and caspase 9 activation. In addition, Bcl2 protein expression was dramatically upregulated in APS pretreated mice (Figure 4(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 ameliorates doxorubicin-induced cardiotoxicity and apoptosis in vivo. (a) H&E staining of normal mice (Con) and mice with doxorubicin-induced heart failure (HF) (n = 5). (b) Representative TUNEL staining of apoptotic cells in normal and doxorubicin-induced heart injury samples. Red staining indicates TUNEL-positive cells (n = 5, *P < 0.05, **P < 0.01). (c) Western blotting and average data for caspase 3, caspase 9, and Bcl2 in sham, doxorubicin-induced heart injury mice (DOX), and mice with APS pretreatment followed by doxorubicin treatment (APS + DOX) (n = 15, **P < 0.01, ***P < 0.001). (d) Mouse heart function 5 days after doxorubicin injection as shown by fractional shortening % (FS %) and ejection fraction % (EF %) (n = 8, *P < 0.05, **P < 0.01).
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Related In: Results  -  Collection

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fig4: APS ameliorates doxorubicin-induced cardiotoxicity and apoptosis in vivo. (a) H&E staining of normal mice (Con) and mice with doxorubicin-induced heart failure (HF) (n = 5). (b) Representative TUNEL staining of apoptotic cells in normal and doxorubicin-induced heart injury samples. Red staining indicates TUNEL-positive cells (n = 5, *P < 0.05, **P < 0.01). (c) Western blotting and average data for caspase 3, caspase 9, and Bcl2 in sham, doxorubicin-induced heart injury mice (DOX), and mice with APS pretreatment followed by doxorubicin treatment (APS + DOX) (n = 15, **P < 0.01, ***P < 0.001). (d) Mouse heart function 5 days after doxorubicin injection as shown by fractional shortening % (FS %) and ejection fraction % (EF %) (n = 8, *P < 0.05, **P < 0.01).
Mentions: To determine whether APS could preserve heart function in vivo, we next generated a heart failure model using doxorubicin-treated C57BL/6 mice. As shown by H&E staining, doxorubicin-induced heart failure was associated with decreased thickening of the left ventricular wall and ventricular dilation (Figure 4(a)). The number of apoptotic cells was dramatically higher in hearts of doxorubicin-treated C57BL/6 mice (26.44 ± 7.72%) compared with hearts from control mice (2.55 ± 0.65%) as demonstrated by TUNEL staining. Importantly, pretreatment with APS attenuated doxorubicin-induced cardiomyocyte apoptosis (15.54 ± 6.06%) (Figure 4(b)). Moreover, Western blot analysis revealed that APS suppressed doxorubicin-induced caspase 3 and caspase 9 activation. In addition, Bcl2 protein expression was dramatically upregulated in APS pretreated mice (Figure 4(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