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Monoamine oxidase B gene deletion prevents cardiac pump dysfunction in mice with pressure overload
Author(s) -
Kaludercic Nina,
Takimoto Eiki,
Nagayama Takahiro,
Lai Edwin,
Chen Kevin,
Shih Jean C,
Pacak Karel,
Kass David A,
Di Lisa Fabio,
Paolocci Nazareno
Publication year - 2010
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.24.1_supplement.573.7
Subject(s) - medicine , pressure overload , endocrinology , ventricle , monoamine oxidase , heart failure , chemistry , cardiac function curve , ejection fraction , monoamine oxidase b , enzyme , biochemistry , cardiac hypertrophy
Monoamine oxidase A (MAO‐A) inhibition prevents pressure overload‐induced congestive heart failure (CHF), decreasing oxidative stress due to MAO‐catalyzed degradation of norepinephrine (NE) and rescuing sympathetic NE content (Kaludercic et al., Circ. Res., 2009). MAO‐B is the major isoform present in the mouse myocardium responsible for catabolism of both NE and dopamine (DA), both endowed with cardiostimulatory effects. Yet whether it contributes to CHF unfolding is unclear. WT and MAO‐B knockout mice (MAO‐B −/− ) were subjected to CHF via transverse aortic constriction (TAC, 9 weeks). LV function was assessed by pressure‐volume (PV) analysis. After TAC, WT hearts had increased left ventricle (LV) dimensions and impaired function accompanied by markedly lower levels of tyrosine hydroxylase, the rate limiting enzyme in DA biosynthesis. Conversely, MAO‐B −/− mice showed preserved end‐systolic (ESV) and end‐diastolic (EDV) volumes and improved LV function: ESV was 5.5±0.8 in MAO‐B −/− vs 16.6±4.5 μl in WT and ejection fraction was 79±1 vs 59±8% in WT (both p<0.01). MAO‐B −/− mice had increased basal DA content. DA (1mM) directly applied to WT isolated cardiac myocytes markedly increased sarcomere shortening (+78%, p<0.05), improving relaxation (−15%, p<0.05). In conclusion, MAO‐B activity shapes basal cardiac function and when inhibited prevents LV remodeling, thus sustaining inotropy in failing hearts.