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

  • Toxicol Appl Pharmacol. 2018 Apr 15;345:1-9. doi: 10.1016/j.taap.2018.03.006.
Fang Qiu  1 ,  Changjiang Dong  1 ,  Yanxin Liu  1 ,  Xiaoqi Shao  1 ,  Di Huang  1 ,  Yanna Han  1 ,  Bing Wang  1 ,  Yanli Liu  1 ,  Rong Huo  1 ,  Petro Paulo  1 ,  Zhi-Ren Zhang  2 ,  Dan Zhao  3 ,  Wen-Feng Chu  4
Affiliations
  • 1. Department of Pharmacology (the State-Province Key Laboratories of Biomedicine-Pharmaceutics of China, Key Laboratory of Cardiovascular Research, Ministry of Education), College of Pharmacy, Harbin Medical University, Harbin, Heilongjiang 150081, PR China.
  • 2. Department of Cardiology and Clinic Pharmacy, Harbin Medical University Cancer Hospital, Institute of Metabolic Disease, Heilongjiang Academy of Medical Science, PR China.
  • 3. Departments of Clinical Pharmacy and Cardiology, The 2nd Affiliated Hospital, Harbin Medical University, Key Laboratories of Education Ministry for Myocardial Ischemia Mechanism and Treatment, Harbin, PR China. Electronic address: [email protected].
  • 4. Department of Pharmacology (the State-Province Key Laboratories of Biomedicine-Pharmaceutics of China, Key Laboratory of Cardiovascular Research, Ministry of Education), College of Pharmacy, Harbin Medical University, Harbin, Heilongjiang 150081, PR China. Electronic address: [email protected].
PMID: 29524504 DOI: 10.1016/j.taap.2018.03.006
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.

Keywords
Cardiac fibrosis; Ginkgolic acid; PML; Pin1; SUMO-1.
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