Novel anti-thrombotic agent for modulation of protein disulfide isomerase family member ERp57 for prophylactic therapy

Guozhen Cui; Luchen Shan; Lin Guo; Ivan Keung Chu; Guohui Li; Quan Quan; Yun Zhao; Cheong Meng Chong; Zaijun Zhang; Pei Yu; Maggie Pui Man Hoi; Yewei Sun; Yuqiang Wang; Simon MingYuen Lee

doi:10.1038/srep10353

Novel anti-thrombotic agent for modulation of protein disulfide isomerase family member ERp57 for prophylactic therapy

Sci Rep. 2015 Jun 3:5:10353. doi: 10.1038/srep10353.

Authors

Guozhen Cui¹, Luchen Shan², Lin Guo³, Ivan Keung Chu⁴, Guohui Li⁴, Quan Quan³, Yun Zhao⁴, Cheong Meng Chong⁵, Zaijun Zhang³, Pei Yu³, Maggie Pui Man Hoi⁵, Yewei Sun³, Yuqiang Wang³, Simon MingYuen Lee⁵

Affiliations

¹ 1] State Key Laboratory of Quality Research in Chinese Medicine and Institute of Chinese Medical Sciences, University of Macau, Macao, China [2] Department of Bioengineering, Zhuhai Campus of Zunyi Medical University, Guangdong, Zhuhai, China.
² 1] Institute of New Drug Research, Collage of Pharmacy, Jinan University, Guangzhou, China [2] Key Laboratory of Cardiovascular Medicine Research, Ministry of Education, Harbin Medical University, Harbin, China.
³ Institute of New Drug Research, Collage of Pharmacy, Jinan University, Guangzhou, China.
⁴ Department of Chemistry, The University of Hong Kong, Hong Kong, China.
⁵ State Key Laboratory of Quality Research in Chinese Medicine and Institute of Chinese Medical Sciences, University of Macau, Macao, China.

Abstract

Protein disulfide isomerase (PDI) family members including PDI and ERp57 emerge as novel targets for anti-thrombotic treatments, but chemical agents with selectivity remain to be explored. We previously reported a novel derivative of danshensu (DSS), known as ADTM, displayed strong cardioprotective effects against oxidative stress-induced cellular injury in vitro and acute myocardial infarct in vivo. Herein, using chemical proteomics approach, we identified ERp57 as a major target of ADTM. ADTM displayed potent inhibitory effects on the redox activity of ERp57, inhibited the adenosine diphosphate (ADP)-induced expressions of P-selectin and αIIbβ3 integrin, and disrupted the interaction between ERp57 and αIIbβ3. In addition, ADTM inhibited both arachidonic acid (AA)-induced and ADP-induced platelet aggregation in vitro. Furthermore, ADTM significantly inhibited rat platelet aggregation and thrombus formation in vivo. Taken together, ADTM represents a promising candidate for anti-thrombotic therapy targeting ERp57.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Adenosine Diphosphate / metabolism
Animals
Blood Platelets / drug effects
Blood Platelets / metabolism
Cell Adhesion Molecules / metabolism
Chlorides / adverse effects
Disease Models, Animal
Enzyme Activation
Ferric Compounds / adverse effects
Fibrinolytic Agents / chemistry
Fibrinolytic Agents / pharmacology*
Gene Expression Regulation / drug effects
Heme Oxygenase-1 / metabolism
Humans
Lactates / chemistry
Lactates / pharmacology
Microfilament Proteins / metabolism
Models, Biological
P-Selectin / genetics
P-Selectin / metabolism
Phosphoproteins / metabolism
Phosphorylation
Platelet Activation
Platelet Aggregation / drug effects
Platelet Glycoprotein GPIIb-IIIa Complex / metabolism
Protein Binding
Protein Disulfide-Isomerases / metabolism*
Proteomics
Rats
Thrombosis / drug therapy
Thrombosis / etiology
Venous Thrombosis / etiology

Substances

Cell Adhesion Molecules
Chlorides
Ferric Compounds
Fibrinolytic Agents
Lactates
Microfilament Proteins
P-Selectin
Phosphoproteins
Platelet Glycoprotein GPIIb-IIIa Complex
vasodilator-stimulated phosphoprotein
3,4-dihydroxyphenyllactic acid
Adenosine Diphosphate
Heme Oxygenase-1
Protein Disulfide-Isomerases
PDIA3 protein, human
ferric chloride