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AuthorSadaf, Riaz
AuthorAbdulrahman, Nabeel
AuthorUddin, Shahab
AuthorJabeen, Ayesha
AuthorGadeau, Alain P.
AuthorFliegel, Larry
AuthorMraiche, Fatima
Available date2023-06-20T10:58:38Z
Publication Date2020-12-05
Publication NameEuropean Journal of Pharmacology
Identifierhttp://dx.doi.org/10.1016/j.ejphar.2020.173420
ISSN00142999
URIhttps://www.sciencedirect.com/science/article/pii/S0014299920305124
URIhttp://hdl.handle.net/10576/44612
AbstractPrevious 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.
Languagear
PublisherElsevier
SubjectCardiomyocytes
Hypertrophy
Autophagy
Cathepsins
Angiotensin
Matrix metalloproteinases
TitleAnti-hypertrophic effect of Na+/H+ exchanger-1 inhibition is mediated by reduced cathepsin B
TypeArticle
Volume Number888
Open Access user License http://creativecommons.org/licenses/by/4.0/
dc.accessType Open Access


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