Abstract
# 89 The serine carboxypeptidase cathepsin a increases atrial fibrillation susceptibility {#article-title-2} 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: In CatA-TG the antioxidant enzyme superoxide dismutase 3 (SOD3) was identified as a cardiac candidate substrate of CatA. This finding was validated by co-expression of recombinant SOD3 and CatA in HEK293 cells. In LV and LA of CatA-TG, highly increased CatA-expression and activity was accompanied by reduced protein levels of SOD3 and more oxidative stress, increased apoptosis and hypertrophy of cardiomyocytes and enhanced collagen expression and fibrosis content. Working heart analysis revealed no changes in LV-function, but susceptibility to atrial fibrillation was increased in CatA-TG. 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. Additionally, SAR1 reduced atrial fibrosis formation as well as lateralization of connexin 43 and attenuated susceptibility to atrial tachyarrhythmias and preserved LA-emptying function. Conclusions: CatA is upregulated in several pathophysiological conditions. We identified the antioxidant enzyme SOD3 as a cardiac substrate of CatA likely underlying oxidative stress associated LA and LV remodeling and increased susceptibility to atria tachyarrhythmias in CatA-TG. The prevention of ventricular and atrial remodeling by the CatA-inhibitor SAR1 in I/R-rats further supports a causal relationship and makes this enzyme a promising target in heart failure and atrial fibrillation.
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