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المؤلفSadaf, Riaz
المؤلفAbdulrahman, Nabeel
المؤلفUddin, Shahab
المؤلفJabeen, Ayesha
المؤلفGadeau, Alain P.
المؤلفFliegel, Larry
المؤلفMraiche, Fatima
تاريخ الإتاحة2023-06-20T10:58:38Z
تاريخ النشر2020-12-05
اسم المنشورEuropean Journal of Pharmacology
المعرّفhttp://dx.doi.org/10.1016/j.ejphar.2020.173420
الرقم المعياري الدولي للكتاب00142999
معرّف المصادر الموحدhttps://www.sciencedirect.com/science/article/pii/S0014299920305124
معرّف المصادر الموحدhttp://hdl.handle.net/10576/44612
الملخصPrevious 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.
اللغةar
الناشرElsevier
الموضوعCardiomyocytes
Hypertrophy
Autophagy
Cathepsins
Angiotensin
Matrix metalloproteinases
العنوانAnti-hypertrophic effect of Na+/H+ exchanger-1 inhibition is mediated by reduced cathepsin B
النوعArticle
رقم المجلد888
Open Access user License http://creativecommons.org/licenses/by/4.0/
dc.accessType Open Access


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