Abstract 3294: Superoxide-Dependent Cathepsin Activation System is Associated with Hypertensive Myocardial Remodeling and Represents a Target for Angiotesin II Type 1 Receptor Blocker Therapy
Objective: Cathepsin (Cat) activation contributes to tissue remodeling, and increased Cat activity and superoxide production has been observed in the left ventricle (LV) during heart failure (HF). In the present study we tested the hypothesis that superoxide-dependnet Cat activation inhibition prevents LV remodeling and dysfunction in the development of HF associated with hypertension.
Methods and Results: We treated 8% salt-loaded Dahl salt-sensitive hypertensive rats (n=10 for each group) with
hydralazine (5 mg/kg/d)
E64d (a synthesis Cat inhibitor, 10 mg/kg/d), or
olmesartan (OLM, 5 mg/kg/d) for 8 weeks.
The rats fed 0.3% salt served as age-matched controls. The abundance of Cat mRNAs and proteins localized in cardiac myocytes (CMCs) and Cat-dependent activities were increased in the LV of HF rats and/or humans, and were reduced by OLM treatment. OLM suppressed the elastic lamina degradation by 56% (n=6, p<0.01) concomitant with decreased local Cat S expression in intracoronary smooth muscle cells (SMCs) and restored the balance of elastin to collagen in the LV tissue of HF rats (HF 4.6 ± 0.9% vs. OLM 15.5 ± 2.1% elastin content/collagen content (%), n=6, P=0.031; control 22 ± 2.1%). Furthermore, OLM suppressed not only angiotensin converting enzyme and angiotensin II type 1 receptor (AT1R) and macrophage infiltration but also levels of NADPH oxidase components (p22phox, gp91 phox, and p47 phox) concomitant with decreased NADPH activity and O2− production in LV tissues of HF rats and humans. These changes were accompanied by improved cardiac fibrosis, stiffness, and dysfunction. Interestingly, LV remodeling and dysfunction were partially improved by treatment with E64d. In vitro, H2O2 stimulated Cat S mRNA and protein expression and activity, and these increases were abolished by pretreatment with MnTmPyp (50 μ mol/L) and N-acetylcysteine (5 mmol/L) as well as apocynin (100 μ mol/L) in culture CMCs (n=6, p<0.01).
Conclusions: This is the first report showing that Cats are likely to trigger and promote LV remodeling, and that AT1R inhibition exerts inhibitory effect on Cat activation system by the inhibition of NADPH oxidase-dependent superoxide anion production, leading to the prevention of cardiac remodeling and dysfunction.