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A Translational Kinetic Analysis of Rodent and Human Hearts Shows Species‐specific Differences and Increases in Monoamine Oxidase Activity with Obesity/Diabetes
Author(s) -
Nelson Margaret,
Katunga Lalage,
Anderson Ethan,
Kypson Alan
Publication year - 2015
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.29.1_supplement.977.7
Subject(s) - monoamine oxidase , medicine , endocrinology , tyramine , monoamine oxidase b , oxidative stress , monoamine neurotransmitter , serotonin , chemistry , reactive oxygen species , enzyme , biology , biochemistry , receptor
Cardiac monoamine oxidase (MAO) has been shown to have an etiological role in heart failure due to the mitochondrial toxicity of the reactive oxygen (ROS) and catechol‐aldehyde species (RCS) produced by this enzyme. A causal role for MAO in cardiomyopathy with obesity and type 2 diabetes has been proposed due to the elevated sympathetic tone that occurs in these conditions, although this has never been investigated in either experimental or clinical models. We performed a cross‐species kinetic analysis of MAO isoform‐specific (A & B) oxidation of dopamine (DA), phenylethylamine (PEA), serotonin (5‐HT), norepinephrine (NE), and Tyramine (TYR) in heart tissue from nondiabetic/control (Ctl) and obese/diabetic (ObD) mice (n=12), rats (n=12), and humans (n=46) using MAO‐derived ROS production as index. In mouse hearts, maximal MAO‐B activity >> MAO‐A, in rat hearts MAO‐A >> MAO‐B, while in humans the isoform activity appears to be equivalent. Maximal MAO activity (both A & B) was significantly higher in ObD mouse and rat hearts with TYR and DA substrates compared with Ctl. ObD mouse hearts also had higher rates of MAO activity with PEA. In human myocardium, MAO activity (both A & B) was 1.5‐fold and 3‐fold higher in ObD patients compared to Ctl patients with NE and DA, respectively. Cardiac MAO‐B activity with 5‐HT also was significantly greater in ObD patients. These translational findings suggest that in obese/diabetic hearts, increased MAO activity and the ROS/RCS derived from it may contribute to cardiomyopathy, and imply that targeting cardiac MAO may have therapeutic potential.