Effect of Extracellular Matrix Stiffness on Candesartan Efficacy in Anti-Fibrosis and Antioxidation

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Studying the Effects of Matrix Stiffness on Cellular Function using Acrylamide-based Hydrogels

Published on: August 10, 2010

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Tong Zhu1,2,3, Jingjing Song1,2, Bin Gao4

  • 1The Key Laboratory of Biomedical Information Engineering of Ministry of Education, School of Life Science and Technology, Xi'an Jiaotong University, Xi'an 710049, China.

Antioxidants (Basel, Switzerland)
|March 29, 2023
PubMed

Insights

Extracellular matrix stiffness significantly impacts Candesartan's efficacy in treating myocardial fibrosis. Medium stiffness showed the best results, highlighting the need to consider mechanical properties in cardiovascular drug development.

Area of Science:

  • Cardiovascular Research
  • Biomaterials Science
  • Pharmacology

Background:

  • Myocardial fibrosis and redox imbalance correlate with extracellular matrix (ECM) stiffness.
  • Candesartan (CAN), an angiotensin II receptor inhibitor, shows anti-fibrosis and antioxidant effects.
  • The influence of ECM stiffness on CAN's therapeutic efficacy is not well understood.

Purpose of the Study:

  • To investigate the impact of ECM stiffness on the efficacy of Candesartan (CAN) in myocardial anti-fibrosis and antioxidant treatment.
  • To establish and utilize mechanical microenvironment models of cardiac fibroblasts (CFs) to assess CAN's effectiveness under varying stiffness conditions.

Main Methods:

  • Constructed rat models with varying myocardial fibrosis and stiffness, treated with CAN.
  • Used polyacrylamide (PA) gels of different stiffness to mimic myocardial ECM stiffness for CF culture.
  • Assessed CF migration, proliferation, activation, reactive oxygen species (ROS), and glutathione (GSH) levels with and without CAN treatment.

Main Results:

  • CAN demonstrated optimal cardiac function improvement and reduced NADPH oxidase-2 (NOX2) levels in rats with medium-stiffness myocardial tissue.
  • CFs cultured on medium-stiffness PA gels showed the most significant anti-fibrosis and antioxidant responses to CAN.
  • ECM stiffness was found to modulate the anti-fibrosis and antioxidant efficacy of CAN.

Conclusions:

  • This study is the first to demonstrate the significant effect of ECM stiffness on the efficacy of Candesartan in myocardial anti-fibrosis and antioxidant treatment.
  • The findings underscore the importance of considering ECM mechanical properties in the development and application of cardiovascular disease therapies.
  • Optimizing drug efficacy for cardiovascular diseases may require tailoring treatments based on the specific mechanical microenvironment of the affected tissue.
Keywords:
candesartan (CAN)extracellular matrix (ECM)myocardial fibrosisoxidative stressscanning electrochemical microscopy (SECM)

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