Abstract
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.
Highlights
Cardiovascular diseases (CVDs) continue to be the major reason for death globally, regardless of the progress in treatment (WHO, 2013)
To verify the role of cathepsin B (Cat B) in the anti-hypertrophic effect of Na+/H+ exchanger isoform-1 (NHE1) inhibition, we examined the effect of the NHE1-specific inhibitor N-[2methyl-4,5-bis(methylsulphonyl)-benzoyl]-guanidine, hydrochloride (EMD, EMD87580; 10 μM) on the hypertrophic phenotype, Cat B protein and mRNA expression, Microtubule-associated protein light chain 3 (LC3)-I/II protein expression and matrix metalloproteinases (MMPs)-9 activity in Ang II-treated H9c2 cardiomyoblasts
Many forms of cathepsins have been proposed to contribute to cardiac hypertrophy (CH), in our study we focused on Cat B, which is stimulated by an acidic pH (Bourguignon et al, 2004; Rozhin et al, 1994), a major stimulus of NHE1 activity
Summary
Cardiovascular diseases (CVDs) continue to be the major reason for death globally, regardless of the progress in treatment (WHO, 2013). Various CVDs including cardiac hypertrophy (CH), hypertension and myocardial infarctions progress to heart failure if left untreated (de Couto et al, 2010; Dupree, 2010). Pathological CH, induced by neurohormonal stimulation, hypertension or myocardial infarctions (MI), is character ized by the increase in size of cardiomyocytes and the remodeling of the extracellular matrix (ECM) (Kang and Izumo, 2003; Kehat and Mol kentin, 2010; Mlih et al, 2015; Watkins et al, 2011). The abnormal stimulation of various ECM proteases including cathepsins and matrix metalloproteinases (MMPs) have been proposed to contribute to the progression of cardiac remodeling (Abdulrahman et al, 2018; Cheng et al, 2012; Dhalla et al, 2009; Rodriguez et al, 2010; Wilson, 2001).
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