Activation of B receptors does not appear to be involved in spontaneous extravasation. Therefore, the assumption that treatment with an ACEi results in an alteration in the physiological vascular barrier function predisposing to non-allergic angio-oedema is not supported by our findings.
Introduction:The serine carboxypeptidase Cathepsin A (CatA) is distributed between lysosomes and extracellular space. Its cardiac expression is upregulated in heart failure patients and in murine models of diabetes, hypertension and myocardial infarction. However, the pathophysiological role of CatA in the heart is unknown. Methods: We developed a heart transgenic mouse model (CatA-TG) to investigate the role of heart specific CatA-overexpression on left ventricular (LV) and atrial (LA) remodeling. Furthermore, in a rat model with ventricular ischemia for 30 min followed by 3 months of reperfusion (I/R-rats), we investigated the effect of the new selective CatA-inhibitor SAR1 on cardiac structural and functional remodeling. Results: Proteomics analysis of the secretome of adult mouse cardiac fibroblasts upon digestion by CatA identified the extracellular antioxidant enzyme superoxide dismutase (EC-SOD) as a novel substrate of CatA. Co-expression of recombinant EC-SOD and CatA in HEK293 cells validated CatA-mediated degradation of EC-SOD. Mice with heart specific CatA overexpression and increased activity (CatA-TG) exhibited a significant decrease in EC-SOD protein and higher levels of oxidative stress in the heart, which was associated with increased apoptosis, hypertrophy of cardiomyocytes and enhanced interstitial fibrosis content. Despite the structural changes, working heart analysis in CatA-TG mice revealed no significant changes in LV-function. In I/R-rats, CatA-inhibition by SAR1 partly attenuated reduction in LV-ejection fraction and preserved regional parameters such as wall thickening and thickness in infarcted and in non-infarcted areas, which was confirmed by histological analysis. Conclusions: Our results show that CatA affects ventricular remodeling and EC-SOD cleavage, independent of LV-dysfunction, and implicate CatA as a potential therapeutic target in heart failure.
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