Catecholamine metabolism via monoamine oxidase (MAO) within myocardium of individuals with type 2 diabetes

ECU Author/Contributor (non-ECU co-authors, if there are any, appear on document)

Margaret A. M. Nelson (Creator)

Institution

East Carolina University (ECU )

Web Site: http://www.ecu.edu/lib/

Abstract: The primary comorbidity and cause of mortality in type 2 diabetes is cardiovascular disease. The structural and the functional cardiac remodeling observed in patients with type 2 diabetes has been shown to be driven by a plethora of mechanisms including mitochondrial dysfunction and oxidative stress. Monoamine oxidase (MAO) , an enzyme located on the outer mitochondrial membrane , catabolizes catecholamines to produce two reactive byproducts upon substrate deamination: catechol-aldehyde and H2O2. We hypothesized that within environments of decreased redox buffering capacity like type 2 diabetes , these byproducts of MAO metabolism disrupt mitochondrial respiration and further drive redox imbalance. Furthermore , we hypothesized that the antioxidant and aldehyde scavenging capacity of carnosine could mitigate the reactivity of MAO-derived byproducts. A comprehensive analysis of catecholamine metabolism was performed in atrial myocardium from individuals with and without type 2 diabetes. MAO-A and-B maximal activity and expression were significantly increased within myocardium from individuals with diabetes and correlated with BMI. MAO-dependent metabolism of norepinephrine decreased ATP production within myocardium from individuals with type 2 diabetes. In addition , decreased aldehyde dehydrogenase and increased basal levels of catechol-protein adducts were observed within this metabolic group. Metabolomic analysis of atrial tissue from individuals with diabetes showed decreased catecholamine levels in the myocardium , supporting an increased flux through MAOs. As a proof of concept of our second hypothesis we showed that carnosine was able to sequester DOPAL , the dopamine-derived catecholaldehyde. Carnosine also attenuated DOPAL-dependent decrease in state 3 respiration in permeabilized fibers isolated from atria. Furthermore , the production of catechol-modified proteins was mitigated by carnosine in a concentration dependent manner. In conclusion , these findings illustrate a pathogenic mechanism for MAO within type 2 diabetes , and suggest that MAO-derived byproducts , especially catecholaldehydes , contribute to redox imbalance and altered mitochondrial bioenergetics observed in myocardium of individuals with type 2 diabetes. In addition , this translational study provides a mechanistic framework for the study of carnosine or related aldehyde scavengers as therapeutic approach for the prevention of cardiac dysfunction in patients with type 2 diabetes.

Additional Information

Publication

Dissertation

Language: English

Date: 2019

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