Matrine improves diabetic cardiomyopathy through TGF-β-induced protein kinase RNA-like endoplasmic reticulum kinase signaling pathway

J Cell Biochem. 2019 Aug;120(8):13573-13582. doi: 10.1002/jcb.28632. Epub 2019 Apr 2.

Abstract

Background: Matrine might play a vital role in cardiovascular diseases progression and treatment.

Objectives: We aimed to explore the protective effects and potential mechanism of matrine against diabetic cardiomyopathy (DCM) in rat model.

Method: A rat model of DCM was induced by streptozotocin, which were then divided into two groups and treated with matrine. Inflammatory cytokines were investigated in serum and myocardial cells after matrine administration. The effects of matrine on cardiac reactive oxygen species (ROS) generation, Malondialdehyde (MDA) levels, and Glutathione peroxidase (GPx), PPARγ1 activity were detected in myocardial cells. The protein kinase RNA-like endoplasmic reticulum kinase (PERK) signal pathway in endoplasmic reticulum stress was studied to elaborated protective effects of matrine in DCM rat by Western blot analysis. Fasting blood glucose and hemodynamic parameters were analyzed after treatment with matrine.

Results: Matrine-inhibited expression levels of inflammatory cytokines of tumor necrosis factor alpha (TNF-α) and interleukin 6. Matrine administration decreased ROS generation, MDA, and transforming growth factor beta levels, and Peroxisome proliferator-activated receptor beta (PPARβ) and Peroxisome proliferator-activated receptorγ 1 (PPARγ1) activity. Matrine administration also significantly inhibited PERK expression. Endogenic expression of PERK canceled matrine-induced apoptosis of myocardial cells. Notably, treatment with matrine significantly decreased nonfasting blood glucose levels and improved hemodynamic parameters of DCM rat.

Conclusions: Matrine may be a promising agent for the treatment of DCM.

Keywords: apoptosis; diabetic cardiomyopathy (DCM); endoplasmic reticulum (ER) stress; matrine; protein kinase RNA-like endoplasmic reticulum kinase expression (PERK) pathway; transforming growth factor beta (TGF-β).

MeSH terms

  • Alkaloids / pharmacology*
  • Animals
  • Apoptosis / drug effects
  • Diabetes Mellitus, Experimental / drug therapy*
  • Diabetes Mellitus, Experimental / genetics
  • Diabetes Mellitus, Experimental / pathology
  • Diabetic Cardiomyopathies / drug therapy*
  • Diabetic Cardiomyopathies / genetics
  • Diabetic Cardiomyopathies / pathology
  • Endoplasmic Reticulum / drug effects
  • Endoplasmic Reticulum / genetics
  • Endoplasmic Reticulum Stress / drug effects
  • Humans
  • Malondialdehyde / metabolism
  • Matrines
  • Myocardium / metabolism
  • Myocardium / pathology
  • PPAR gamma / genetics
  • Protein Kinases / genetics
  • Quinolizines / pharmacology*
  • RNA / genetics
  • Rats
  • Reactive Oxygen Species / metabolism
  • Signal Transduction / drug effects
  • Transforming Growth Factor beta / genetics*
  • eIF-2 Kinase / genetics

Substances

  • Alkaloids
  • PPAR gamma
  • Quinolizines
  • Reactive Oxygen Species
  • Transforming Growth Factor beta
  • Malondialdehyde
  • RNA
  • Protein Kinases
  • EIF2AK3 protein, human
  • eIF-2 Kinase
  • Matrines