Manara - Qatar Research Repository
1-s2.0-S0014299920305124-main.pdf (4.32 MB)

Anti-hypertrophic effect of Na+/H+ exchanger-1 inhibition is mediated by reduced cathepsin B

Download (4.32 MB)
journal contribution
submitted on 2023-10-08, 10:42 and posted on 2023-10-08, 11:38 authored by Sadaf Riaz, Nabeel Abdulrahman, Shahab Uddin, Ayesha Jabeen, Alain P. Gadeau, Larry Fliegel, Fatima Mraiche

Previous studies have established the role of Na+/H+ exchanger isoform-1 (NHE1) and cathepsin B (Cat B) in the development of cardiomyocyte hypertrophy (CH). Both NHE1 and Cat B are activated under acidic conditions suggesting that their activities might be interrelated. The inhibition of NHE1 has been demonstrated to reduce cardiac hypertrophy but the mechanism that contributes to the anti-hypertrophic effect of NHE1 inhibition still remains unclear. H9c2 cardiomyoblasts were stimulated with Angiotensin (Ang) II in the presence and absence of N-[2-methyl-4,5-bis(methylsulphonyl)-benzoyl]-guanidine, hydrochloride (EMD, EMD 87580), an NHE1 inhibitor or CA-074Me, a Cat B inhibitor, and various cardiac hypertrophic parameters, namely cell surface area, protein content and atrial natriuretic peptide (ANP) mRNA were analyzed. EMD significantly suppressed markers of cardiomyocyte hypertrophy and inhibited Ang II stimulated Cat B protein and gene expression. Cat B is located within the acidic environment of lysosomes. Cat B proteases are released into the cytoplasm upon disintegration of the lysosomes. EMD or CA-074Me prevented the dispersal of the lysosomes induced by Ang II and reduced the ratio of LC3-II to LC3-I, a marker of autophagy. Moreover, Cat B protein expression and MMP-9 activity in the extracellular space were significantly attenuated in the presence of EMD or CA-074Me. Our study demonstrates a novel mechanism for attenuation of the hypertrophic phenotype by NHE1 inhibition that is mediated by a regression in Cat B. The inhibition of Cat B via EMD or CA-074Me attenuates the autosomal-lysosomal pathway and MMP-9 activation.

Other Information

Published in: European Journal of Pharmacology
See article on publisher's website:


Open Access funding provided by the Qatar National Library



  • English



Publication Year

  • 2020

License statement

This Item is licensed under the Creative Commons Attribution 4.0 International License

Institution affiliated with

  • Qatar University
  • Qatar University Health - QU
  • College of Pharmacy - QU HEALTH
  • Hamad Medical Corporation

Usage metrics

    Qatar University



    Ref. manager