Atrial fibrillation (AF) is a debilitating cardiovascular disease that doubles in frequency with each decade of life over age 50. In addition to aging, several reports have documented a significant increase (>2-fold) in AF risk with obesity and type 2 diabetes. Pathophysiologic mechanisms underlying AF remain mostly obscure, although clinical and experimental evidence suggests that diabetes and AF share pathogenic factors in the heart that may become unmasked, or exacerbated, by the natural process of aging. Sympathetic tone and oxidative stress are increased with aging and obesity/diabetes, and most importantly, these are known to be pathogenic factors in AF. We have recently shown that monoamine oxidase (MAO) appears to be a major contributor to oxidative stress in the atrial myocardium and that MAO activity is associated with post-operative AF. Importantly, our lab also has observed increased MAO content and activity in atrial myocardium from diabetic patients. MAO metabolizes norepinephrine (NE) and dopamine (DA) to produce 3,4-dihydroxyphenylglycolaldehyde (DOPEGAL) and 3,4-dihydroxyphenylacetaldehyde (DOPAL), respectively, and H2O2. Products of oxidative stress potently inhibit further metabolism of these two catecholaldehydes by aldo-keto reductase (AKR) and aldehyde dehydrogenase (ALDH). Both DOPEGAL and DOPAL have been shown to be very cytotoxic due to the reactivity of both catechol and aldehyde groups on these molecules. Despite the plausible role of MAO in cardiovascular injury, to the best of our knowledge no evidence of these catecholaldehydes in the myocardium has been reported. This exploratory project combines the expertise and resources of an analytical chemist/toxicologist (Doorn) with a cardio-metabolic/mitochondrial physiologist (Anderson) in order to 1) determine the mechanisms of catecholaldehyde production, metabolism, and toxicity in human atrial myofibers and fibroblasts; and 2) develop a sensitive LC-MS/MS approach to quantify biomarkers for elevated DOPAL- and DOPEGAL in human blood and atrial tissue, including catecholaldehyde-protein adducts and downstream metabolites of these aldehydes. To accomplish these objectives, we will leverage samples from the human atrial tissue repository procured in Dr. Anderson's laboratory as part of another project.
In Aim 1, we will test the hypothesis that the content and/or enzymatic activities of AKR and ALDH2 are decreased with diabetes and/or aging, leading to enhanced catecholaldehyde production and toxicity.
In Aim 2, we will test the hypothesis that catecholaldehyde adducts in blood and myocardium are associated with MAO activity and plasma catecholamine concentrations. It is expected that this project may ultimately lead to important follow-on studies examining the link between adrenergic system, catecholaldehydes and cardiotoxicity, and to development of novel treatments and screening methods for AF and other cardiovascular disorders that are common in aged and diabetic patient populations.
Atrial fibrillation (AF), an irregular heartbeat occurring in the upper compartments of the heart, is a chronic and debilitating cardiovascular disease that commonly occurs in aged and diabetic individuals. This project seeks to test a completely new theory that reactive molecules derived from the metabolism of norepinephrine and dopamine may be toxic to the heart, and also seeks to develop a sensitive way of measuring these molecules in blood samples. We expect that this knowledge and new technology may ultimately pave the way toward development of new treatments and screening methods for AF, and perhaps other cardiovascular disorders that are common to aged and diabetic individuals.
| Stein, Colleen S; Jadiya, Pooja; Zhang, Xiaoming et al. (2018) Mitoregulin: A lncRNA-Encoded Microprotein that Supports Mitochondrial Supercomplexes and Respiratory Efficiency. Cell Rep 23:3710-3720.e8 |
| Nelson, Margaret-Ann M; Builta, Zachariah J; Monroe, T Blake et al. (2018) Biochemical characterization of the catecholaldehyde reactivity of L-carnosine and its therapeutic potential in human myocardium. Amino Acids : |
