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

Abstract

BACKGROUND AND PURPOSE:

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).

EXPERIMENTAL APPROACH:

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.

KEY RESULTS:

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.

CONCLUSIONS AND IMPLICATIONS:

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.

• Authors: Fang Qiu, Changjiang Dong, Yanxin Liu, Xiaoqi Shao, Di Huang, Yanna Han, Bing Wang, Yanli Liu, Rong Huo, Petro Paulo, Zhi-Ren Zhang, Dan Zhao, Wen-Feng Chu
• Journal: Toxicology and applied pharmacology (Toxicol Appl Pharmacol) Vol. 345 Pg. 1-9 (04 15 2018) ISSN: 1096-0333 [Electronic] United States
• PMID: 29524504 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2018. Published by Elsevier Inc.

Chemical References

• SUMO-1 Protein
• Salicylates
• ginkgolic acid

Topics

• Animals
• Animals, Newborn
• Cell Survival (drug effects, physiology)
• Dose-Response Relationship, Drug
• Fibrosis (drug therapy, metabolism, pathology)
• Male
• Mice
• Myocardial Infarction (drug therapy, metabolism, pathology)
• SUMO-1 Protein (antagonists & inhibitors, metabolism)
• Salicylates (pharmacology, therapeutic use)
• Stroke Volume (drug effects, physiology)