Pharmacological inhibition of SUMO-1 with ginkgolic acid alleviates cardiac fibrosis induced by myocardial infarction in mice

• Published in: Toxicology and applied pharmacology 2018-04, Vol.345, p.1-9
• Main Authors: Qiu, Fang, Dong, Changjiang, Liu, Yanxin, Shao, Xiaoqi, Huang, Di, Han, Yanna, Wang, Bing, Liu, Yanli, Huo, Rong, Paulo, Petro, Zhang, Zhi-Ren, Zhao, Dan, Chu, Wen-Feng
• Format: Article
• Language: English
• Subjects: Animals; Animals, Newborn; Cardiac fibrosis; Cell Survival - drug effects; Cell Survival - physiology; Dose-Response Relationship, Drug; Fibrosis - drug therapy; Fibrosis - metabolism; Fibrosis - pathology; Ginkgolic acid; Male; Mice; Myocardial Infarction - drug therapy; Myocardial Infarction - metabolism; Myocardial Infarction - pathology; Pin1; PML; Salicylates - pharmacology; Salicylates - therapeutic use; Stroke Volume - drug effects; Stroke Volume - physiology; SUMO-1; SUMO-1 Protein - antagonists & inhibitors; SUMO-1 Protein - metabolism
• ISSN: 0041-008X; 1096-0333
• DOI: 10.1016/j.taap.2018.03.006

Protein modification by small ubiquitin-like modifier (SUMO) plays a critical role in the pathogenesis of heart diseases. The present study was designed to determine whether ginkgolic acid (GA) as a SUMO-1 inhibitor exerts an inhibitory effect on cardiac fibrosis induced by myocardial infarction (MI). GA was delivered by osmotic pumps in MI mice. Masson staining, electron microscopy (EM) and echocardiography were used to assess cardiac fibrosis, ultrastructure and function. Expression of SUMO-1, PML, TGF-β1 and Pin1 was measured with Western blot or Real-time PCR. Collagen content, cell viability and myofibroblast transformation were measured in neonatal mouse cardiac fibroblasts (NMCFs). Promyelocytic leukemia (PML) protein was over-expressed by plasmid transfection. GA improved cardiac fibrosis and dysfunction, and decreased SUMO-1 expression in MI mice. GA (>20 μM) inhibited NMCF viability in a dose-dependent manner. Nontoxic GA (10 μM) restrained angiotensin II (Ang II)-induced myofibroblast transformation and collagen production. GA also inhibited expression of TGF-β1 mRNA and protein in vitro and in vivo. GA suppressed PML SUMOylation and PML nuclear body (PML-NB) organization, and disrupted expression and recruitment of Pin1 (a positive regulator of TGF-β1 mRNA), whereas over-expression of PML reversed that. Inhibition of SUMO-1 by GA alleviated MI-induced heart dysfunction and fibrosis, and the SUMOylated PML/Pin1/TGF-β1 pathway is crucial for GA-inhibited cardiac fibrosis. Under pathological conditions, PML SUMOylation process is enhanced, which promotes PML-NBs organization, accompanied by increased recruitment of Pin1 into NBs. Pin1 which translocates to the nucleus can isomerize AUF1, thereby protecting TGF-β1 mRNAagainst decay progress. However, GA treatment impairs E1-SUMO conjugation, inhibiting PML SUMOylation and NB organization. The decrease in number and size of PML-NBs causes reduction of the expression and recruitment of Pin1. Thus, TGF-β1 mRNA degrades and fibrosis is alleviated. [Display omitted] •GA alleviates MI-induced cardiac dysfunction and fibrosis.•The SUMO-1/PML/Pin1 axis is critical for GA-inhibited cardiac fibrosis.•SUMO-1 is a potential therapeutic target for cardiac fibrosis.