Plin5/p-Plin5 Guards Diabetic CMECs by Regulating FFAs Metabolism Bidirectionally

Author:

Du Jin1,Hou Juanni2,Feng Juan1,Zhou Hong3,Zhao Heng4,Yang Dachun1ORCID,Li De1,Yang Yongjian1ORCID,Pei Haifeng1ORCID

Affiliation:

1. Department of Cardiology, The General Hospital of Western Theater Command, Chengdu 610083, China

2. Department of Gastroenterology, The General Hospital of Western Theater Command, Chengdu 610083, China

3. Department of Respiration, The General Hospital of Western Theater Command, Chengdu 610083, China

4. Department of Function, Sichuan Petroleum General Hospital, Chengdu 610212, China

Abstract

Background. Hyper-free fatty acidemia (HFFA) impairs cardiac capillaries, as well as type 2 diabetes mellitus (T2DM). Perilipin 5 (Plin5) maintains metabolic balance of free fatty acids (FFAs) in high oxidative tissues via the states of nonphosphorylation and phosphorylation. However, when facing to T2DM-HFFA, Plin5’s role in cardiac microvascular endothelial cells (CMECs) is not defined. Methods. In mice of WT or Plin5-/-, T2DM models were rendered by high-fat diet combined with intraperitoneal injection of streptozocin. CMECs isolated from left ventricles were incubated with high glucose (HG) and high FFAs (HFFAs). Plin5 phosphorylation was stimulated by isoproterenol. Plin5 expression was knocked down by small interfering RNA (siRNA). We determined cardiac function by small animal ultrasound, apoptotic rate by flow cytometry, microvessel quantity by immunohistochemistry, microvascular integrity by scanning electron microscopy, intracellular FFAs by spectrophotometry, lipid droplets (LDs) by Nile red staining, mRNAs by quantitative real-time polymerase chain reaction, proteins by western blots, nitric oxide (NO) and reactive oxygen species (ROS) by fluorescent dye staining and enzyme-linked immunosorbent assay kits. Results. In CMECs, HFFAs aggravated cell injury induced by HG and activated Plin5 expression. In mice with T2DM-HFFA, Plin5 deficiency reduced number of cardiac capillaries, worsened structural incompleteness, and enhanced diastolic dysfunction. Moreover, in CMECs treated with HG-HFFAs, both ablation and phosphorylation of Plin5 reduced LDs content, increased intracellular FFAs, stimulated mitochondrial β-oxidation, added ROS generation, and reduced the expression and activity of endothelial nitric oxide synthase (eNOS), eventually leading to increased apoptotic rate and decreased NO content, all of which were reversed by N-acetyl-L-cysteine. Conclusion. Plin5 preserves lipid balance and cell survival in diabetic CMECs by regulating FFAs metabolism bidirectionally via the states of nonphosphorylation and phosphorylation.

Funder

China Postdoctoral Science Foundation

Publisher

Hindawi Limited

Subject

Cell Biology,Aging,General Medicine,Biochemistry

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