Journal
EUROPEAN JOURNAL OF PHARMACOLOGY
Volume 855, Issue -, Pages 183-191Publisher
ELSEVIER SCIENCE BV
DOI: 10.1016/j.ejphar.2019.05.003
Keywords
Protocatechualdehyde; Myocardial fibrosis; Target identification; Collagen; Conformational dynamics
Categories
Funding
- National Natural Science Foundation of China [81530097, 81222051, 81773932]
- National Key Technology R&D Program New Drug Innovation of China [2017ZX09101003-008-003, 2018ZX09711001-008-003]
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Myocardial fibrosis is associated with cardiovascular remodeling, which is characterized by abnormal collagen architecture. However, there are not yet effective strategies targeting this abnormal pathological process. The purpose of our study is to investigate the effect of protocatechualdehyde (PCA) on myocardial fibrosis for exploring the underlying target protein and molecular mechanism. We found PCA significantly suppressed isoprenaline (ISO)-induced fibrosis and collagen deposition in myocardial tissue. Then, the direct pharmacological target of PCA was identified as collagen I using cellular thermal shift assay (CETSA) coupled with stable isotope labeling with amino acids in cell culture (SILAC) technology. Surface plasmon resonance (SPR) analysis further confirmed the specific binding of PCA with collagen I. Moreover, collagen self-assembly assay and atomic force microscope analysis confirmed that PCA directly modulated collagen conformational dynamics. LC-MS/MS analysis was applied to determine lysine residues as the binding sites of PCA on collagen I by covalently cross-linking reaction. Collectively, our study suggests that PCA controls cardiovascular remodeling by mediating diffuse interstitial myocardial fibrosis. Moreover, directly targeting collagen may be a promising strategy for the treatment of heart failure and resultant myocardial fibrosis.
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