Cardiotoxicity of catecholamine metabolism by monoamine oxidase with obesity

The National Heart, Lung, and Blood Institute awarded The University of Iowa $143,080 on December 6, 2025, under the Cardiovascular Diseases Research program (CFDA 93.837) to support research into the cardiotoxic effects of monoamine oxidase (MAO) metabolism of catecholamines in obesity.

The award funds a dissertation project investigating how three reactive metabolites produced by MAO—hydrogen peroxide, ammonia, and catecholaldehydes—individually contribute to mitochondrial dysfunction and electromechanical heart failure in diet-induced obesity. The research employs genetic approaches (cardiomyocyte-specific MAO-A deficiency) and pharmacological intervention (oral carnosine therapy) to test whether reducing production of these metabolites provides cardioprotection. The project addresses a knowledge gap regarding the targets and mechanisms of metabolite toxicity, which must be resolved before therapeutic development can proceed. Prior work from the recipient's laboratory demonstrated that MAO activity increases while catecholaldehyde-detoxifying enzyme activity decreases in hearts with obesity and insulin resistance, leading to reactive metabolite accumulation, mitochondrial ATP depletion, and pro-inflammatory and pro-fibrotic signaling; carnosine mitigates these effects by neutralizing reactive molecules.

Performance occurs in Iowa City, Iowa, with a period of performance from December 6, 2025, through June 4, 2027. The assistance type is Project Grant.

Abstract

Monoamine oxidase (MAO) is a mitochondria-localized enzyme that metabolizes catecholamines via oxidative deamination to produce H2O2, NH4+, and catecholaldehydes, each of which may individually induce toxicity and/or lead to secondary metabolic effects in the cell. Our lab and others have demonstrated the pathophysiological significance of MAO in heart with experimental and clinical models of pressure overload, arrhythmia, and diabetes. Obesity and insulin resistance are widespread and growing metabolic disorders known to be linked to cardiomyopathy, and previous work from our lab has shown that MAO activity increases while catecholaldehyde-detoxifying enzyme decreases in the heart with these disorders, leading to a buildup of reactive metabolites causing derangements in mitochondrial ATP production. We have also shown that catecholaldehydes stimulate pro-inflammatory and pro-fibrotic signaling in the heart, and that the histidyl dipeptide carnosine mitigates these effects by neutralizing these reactive molecules. Together, this suggests a significant role for MAO in obesity/insulin resistance-associated cardiomyopathy, although the targets and mechanisms driving the metabolite toxicity are unknown, largely due to the highly reactive nature of these molecules and difficulties associated with their detection. These knowledge gaps must be addressed in order for therapeutic development to proceed. In this project i will test the hypothesis that all 3 of MAO's reactive metabolites (i.e., H2O2, NH4+, and catecholaldehydes) contribute individually to mitochondrial abnormalities and electromechanical dysfunction in heart with diet-induced obesity, and reducing their production in cardiomyocytes via genetic (i.e., cardiomyocyte-specific MAO-a deficiency, cmao-adef) and pharmacological approaches (i.e., oral carnosine therapy) will be cardioprotective. As part of my dissertation project i have recently developed a sensitive LC-MS/MS method to detect and quantify catecholaldehyde-carnosine adducts in biological material, which will be used as a quantitative biomarker to track effectiveness of MAO inhibition and carnosine efficacy in the mouse models employed. I will accomplish the goals of this research through three specific aims using wild-type and cmao-adef mice on normal chow and high FAT, high sucrose diet. In aim 1, i will determine the extent to which cardiomyocyte MAO-a deficiency mitigates derangements in myocardial structure, tissue composition and function with obesity/insulin-resistance. In aim 2, i will determine the mechanisms by which MAO metabolites contributes to mitochondrial abnormalities in the heart with obesity/insulin-resistance. In aim 3, i will interrogate molecular targets of catecholaldehydes and MAO- dependent oxidative damage in the hearts of obese/insulin-resistant mice. To accomplish these goals, i will work with an interdisciplinary team of toxicologists and cardiovascular physiologists and the core facilities at the university of iowa. IT is anticipated that my project will advance the fields of toxicology and molecular cardiology, and illustrate pathways by which MAO and its metabolites are viable drug targets in the heart with obesity.