Salvianolic acid A, a matrix metalloproteinase-9 inhibitor of Salvia miltiorrhiza, attenuates aortic aneurysm formation in apolipoprotein E-deficient mice

Tingting Zhang; Jinghua Xu; Defang LI; Jing Chen; Xu Shen; Feng Xu; Fukang Teng; Yanping Deng; Hongmei Ma; Li Zhang; Ge ZHANG; Zhou Zhang; Wanying Wu; Xuan Liu; Min Yang; Baohong Jiang; Den Guo

doi:10.1016/j.phymed.2014.05.003

Salvianolic acid A, a matrix metalloproteinase-9 inhibitor of Salvia miltiorrhiza, attenuates aortic aneurysm formation in apolipoprotein E-deficient mice

Tingting Zhang
, Jinghua Xu
, Defang LI
, Jing Chen
, Xu Shen
, Feng Xu
, Fukang Teng
, Yanping Deng
, Hongmei Ma
, Li Zhang
, Ge ZHANG
, Zhou Zhang
, Wanying Wu
, Xuan Liu
, Min Yang
, Baohong Jiang^*
, Den Guo

^*Corresponding author for this work

Research output: Contribution to journal › Journal article › peer-review

38 Citations (Scopus)

Abstract

Aortic aneurysm (AA) is a life-threatening vascular disease in defect of effective pharmaceutical therapy. Matrix metalloproteinase-9 (MMP-9) is implicated in the development of chronic vascular diseases including aneurysm, but the effective MMP-9 inhibitors are far from development. To develop new candidate for AA therapy, we evaluated the efficiency of salvianolic acid A (SalA), a novel MMP-9 inhibitor, on AA progression in a mouse model and characterized the mechanism of action. SalA is a water soluble compound of the herbal drug Rhizoma Salviae miltiorrhizae (Danshen) which in China is widely used for the treatment of hypertension, coronary artery diseases and myocardial infarction. MMPs activity was evaluated by enzyme kinetic analysis in vitro and in-gel gelatin zymography in vivo. SalA showed selectivity on gelatinase (MMP-2 and MMP-9) than on collagenase (MMP-8 and MMP-13) in vitro, and specificity on MMP-9 than MMP-2 in vivo. Aortic aneurysm was induced by angiotension II (AngII) in apolipoprotein E-deficient (ApoE^-/-) mice. Aortic structure was evaluated by hematoxylin and eosin, picrosirius red, orein stain. Macrophage infiltration was detected by immunohistochemistry in vivo and transwell in vitro. Comparing with doxycycline (Dox), a well-known MMPs inhibitor, SalA showed similar efficiency against AA progression. SalA significantly decreased aortic diameter and aneurysm severity, ameliorated integrity of vascular structure, inhibited elastin fragmentation and macrophage infiltration. Furthermore, SalA showed greater safety than Dox based on hepatotoxicity evaluation. Our results demonstrated that SalA held great potential for AA therapy.

Original language	English
Pages (from-to)	1137-1145
Number of pages	9
Journal	Phytomedicine
Volume	21
Issue number	10
DOIs	https://doi.org/10.1016/j.phymed.2014.05.003
Publication status	Published - 15 Sept 2014

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

SDG 3 Good Health and Well-being

User-Defined Keywords

Aortic aneurysm
Danshen
Doxycycline
Matrix metalloproteinase
Salvia miltiorrhiza
Salvianolic acid A

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10.1016/j.phymed.2014.05.003

Cite this

Zhang, T., Xu, J., LI, D., Chen, J., Shen, X., Xu, F., Teng, F., Deng, Y., Ma, H., Zhang, L., ZHANG, G., Zhang, Z., Wu, W., Liu, X., Yang, M., Jiang, B., & Guo, D. (2014). Salvianolic acid A, a matrix metalloproteinase-9 inhibitor of Salvia miltiorrhiza, attenuates aortic aneurysm formation in apolipoprotein E-deficient mice. Phytomedicine, 21(10), 1137-1145. https://doi.org/10.1016/j.phymed.2014.05.003

@article{de673140ff7a44f8b16a921210ecf585,

title = "Salvianolic acid A, a matrix metalloproteinase-9 inhibitor of Salvia miltiorrhiza, attenuates aortic aneurysm formation in apolipoprotein E-deficient mice",

abstract = "Aortic aneurysm (AA) is a life-threatening vascular disease in defect of effective pharmaceutical therapy. Matrix metalloproteinase-9 (MMP-9) is implicated in the development of chronic vascular diseases including aneurysm, but the effective MMP-9 inhibitors are far from development. To develop new candidate for AA therapy, we evaluated the efficiency of salvianolic acid A (SalA), a novel MMP-9 inhibitor, on AA progression in a mouse model and characterized the mechanism of action. SalA is a water soluble compound of the herbal drug Rhizoma Salviae miltiorrhizae (Danshen) which in China is widely used for the treatment of hypertension, coronary artery diseases and myocardial infarction. MMPs activity was evaluated by enzyme kinetic analysis in vitro and in-gel gelatin zymography in vivo. SalA showed selectivity on gelatinase (MMP-2 and MMP-9) than on collagenase (MMP-8 and MMP-13) in vitro, and specificity on MMP-9 than MMP-2 in vivo. Aortic aneurysm was induced by angiotension II (AngII) in apolipoprotein E-deficient (ApoE-/-) mice. Aortic structure was evaluated by hematoxylin and eosin, picrosirius red, orein stain. Macrophage infiltration was detected by immunohistochemistry in vivo and transwell in vitro. Comparing with doxycycline (Dox), a well-known MMPs inhibitor, SalA showed similar efficiency against AA progression. SalA significantly decreased aortic diameter and aneurysm severity, ameliorated integrity of vascular structure, inhibited elastin fragmentation and macrophage infiltration. Furthermore, SalA showed greater safety than Dox based on hepatotoxicity evaluation. Our results demonstrated that SalA held great potential for AA therapy.",

keywords = "Aortic aneurysm, Danshen, Doxycycline, Matrix metalloproteinase, Salvia miltiorrhiza, Salvianolic acid A",

author = "Tingting Zhang and Jinghua Xu and Defang LI and Jing Chen and Xu Shen and Feng Xu and Fukang Teng and Yanping Deng and Hongmei Ma and Li Zhang and Ge ZHANG and Zhou Zhang and Wanying Wu and Xuan Liu and Min Yang and Baohong Jiang and Den Guo",

note = "Funding Information: This work was supported by National Science \& Technology Major Project for “Key New Drug Creation and Manufacturing Program” ( 2013ZX09103002-024 , 2011ZX09307-002-03 ), National Natural Science Foundation of China Grants ( 81173587 ), Shanghai Science and Technology Development Foundation of Experimental Animal Research Project ( 12140902400 ). This work was also partially supported by Global Research Network for Medicinal Plants (GRNMP) and King Saud University and the National High Technology Research and Development Program (“863” Program) of China ( SS2013AA09002 ) and Twelfth Five-Year National Science \& Technology Support Program ( 2012BAI29B06 ).",

year = "2014",

month = sep,

day = "15",

doi = "10.1016/j.phymed.2014.05.003",

language = "English",

volume = "21",

pages = "1137--1145",

journal = "Phytomedicine",

issn = "0944-7113",

publisher = "Elsevier GmbH",

number = "10",

}

Zhang, T, Xu, J, LI, D, Chen, J, Shen, X, Xu, F, Teng, F, Deng, Y, Ma, H, Zhang, L, ZHANG, G, Zhang, Z, Wu, W, Liu, X, Yang, M, Jiang, B & Guo, D 2014, 'Salvianolic acid A, a matrix metalloproteinase-9 inhibitor of Salvia miltiorrhiza, attenuates aortic aneurysm formation in apolipoprotein E-deficient mice', Phytomedicine, vol. 21, no. 10, pp. 1137-1145. https://doi.org/10.1016/j.phymed.2014.05.003

TY - JOUR

T1 - Salvianolic acid A, a matrix metalloproteinase-9 inhibitor of Salvia miltiorrhiza, attenuates aortic aneurysm formation in apolipoprotein E-deficient mice

AU - Zhang, Tingting

AU - Xu, Jinghua

AU - LI, Defang

AU - Chen, Jing

AU - Shen, Xu

AU - Xu, Feng

AU - Teng, Fukang

AU - Deng, Yanping

AU - Ma, Hongmei

AU - Zhang, Li

AU - ZHANG, Ge

AU - Zhang, Zhou

AU - Wu, Wanying

AU - Liu, Xuan

AU - Yang, Min

AU - Jiang, Baohong

AU - Guo, Den

N1 - Funding Information: This work was supported by National Science & Technology Major Project for “Key New Drug Creation and Manufacturing Program” ( 2013ZX09103002-024 , 2011ZX09307-002-03 ), National Natural Science Foundation of China Grants ( 81173587 ), Shanghai Science and Technology Development Foundation of Experimental Animal Research Project ( 12140902400 ). This work was also partially supported by Global Research Network for Medicinal Plants (GRNMP) and King Saud University and the National High Technology Research and Development Program (“863” Program) of China ( SS2013AA09002 ) and Twelfth Five-Year National Science & Technology Support Program ( 2012BAI29B06 ).

PY - 2014/9/15

Y1 - 2014/9/15

N2 - Aortic aneurysm (AA) is a life-threatening vascular disease in defect of effective pharmaceutical therapy. Matrix metalloproteinase-9 (MMP-9) is implicated in the development of chronic vascular diseases including aneurysm, but the effective MMP-9 inhibitors are far from development. To develop new candidate for AA therapy, we evaluated the efficiency of salvianolic acid A (SalA), a novel MMP-9 inhibitor, on AA progression in a mouse model and characterized the mechanism of action. SalA is a water soluble compound of the herbal drug Rhizoma Salviae miltiorrhizae (Danshen) which in China is widely used for the treatment of hypertension, coronary artery diseases and myocardial infarction. MMPs activity was evaluated by enzyme kinetic analysis in vitro and in-gel gelatin zymography in vivo. SalA showed selectivity on gelatinase (MMP-2 and MMP-9) than on collagenase (MMP-8 and MMP-13) in vitro, and specificity on MMP-9 than MMP-2 in vivo. Aortic aneurysm was induced by angiotension II (AngII) in apolipoprotein E-deficient (ApoE-/-) mice. Aortic structure was evaluated by hematoxylin and eosin, picrosirius red, orein stain. Macrophage infiltration was detected by immunohistochemistry in vivo and transwell in vitro. Comparing with doxycycline (Dox), a well-known MMPs inhibitor, SalA showed similar efficiency against AA progression. SalA significantly decreased aortic diameter and aneurysm severity, ameliorated integrity of vascular structure, inhibited elastin fragmentation and macrophage infiltration. Furthermore, SalA showed greater safety than Dox based on hepatotoxicity evaluation. Our results demonstrated that SalA held great potential for AA therapy.

AB - Aortic aneurysm (AA) is a life-threatening vascular disease in defect of effective pharmaceutical therapy. Matrix metalloproteinase-9 (MMP-9) is implicated in the development of chronic vascular diseases including aneurysm, but the effective MMP-9 inhibitors are far from development. To develop new candidate for AA therapy, we evaluated the efficiency of salvianolic acid A (SalA), a novel MMP-9 inhibitor, on AA progression in a mouse model and characterized the mechanism of action. SalA is a water soluble compound of the herbal drug Rhizoma Salviae miltiorrhizae (Danshen) which in China is widely used for the treatment of hypertension, coronary artery diseases and myocardial infarction. MMPs activity was evaluated by enzyme kinetic analysis in vitro and in-gel gelatin zymography in vivo. SalA showed selectivity on gelatinase (MMP-2 and MMP-9) than on collagenase (MMP-8 and MMP-13) in vitro, and specificity on MMP-9 than MMP-2 in vivo. Aortic aneurysm was induced by angiotension II (AngII) in apolipoprotein E-deficient (ApoE-/-) mice. Aortic structure was evaluated by hematoxylin and eosin, picrosirius red, orein stain. Macrophage infiltration was detected by immunohistochemistry in vivo and transwell in vitro. Comparing with doxycycline (Dox), a well-known MMPs inhibitor, SalA showed similar efficiency against AA progression. SalA significantly decreased aortic diameter and aneurysm severity, ameliorated integrity of vascular structure, inhibited elastin fragmentation and macrophage infiltration. Furthermore, SalA showed greater safety than Dox based on hepatotoxicity evaluation. Our results demonstrated that SalA held great potential for AA therapy.

KW - Aortic aneurysm

KW - Danshen

KW - Doxycycline

KW - Matrix metalloproteinase

KW - Salvia miltiorrhiza

KW - Salvianolic acid A

UR - https://www.scopus.com/pages/publications/84904974907

U2 - 10.1016/j.phymed.2014.05.003

DO - 10.1016/j.phymed.2014.05.003

M3 - Journal article

C2 - 24916705

AN - SCOPUS:84904974907

SN - 0944-7113

VL - 21

SP - 1137

EP - 1145

JO - Phytomedicine

JF - Phytomedicine

IS - 10

ER -

Salvianolic acid A, a matrix metalloproteinase-9 inhibitor of Salvia miltiorrhiza, attenuates aortic aneurysm formation in apolipoprotein E-deficient mice

Abstract

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