Abstract
Spontaneous generation of reactive sugar‐ and lipid‐derived aldehydes occurs in vivo as a byproduct of oxidative stress, and these aldehydes form protein adducts via electrophilic attack on cysteine and lysine residues. Catecholaldehydes are biogenic aldehydes formed as products of catecholamine metabolism by monoamine oxidase (MAO). MAO catalyzes the oxidative deamination of dopamine to generate 3,4‐dihydroxyphenylacetaldehyde (DOPAL), a reactive molecule that has been shown to be neurotoxic stemming from the reactivity of both catechol and aldehyde groups. Our lab has recently reported that diabetic patients have higher content and activity of MAO in atrial myocardium as compared with age‐matched nondiabetic patients, and that MAO activity in this tissue is associated with postoperative atrial fibrillation. Increased collagen deposition in the heart (i.e., fibrosis) is a well‐known risk factor for arrhythmias, and is also associated with diabetes. Here, we tested the hypothesis that DOPAL‐adducts induce production and secretion of collagen in human cardiac fibroblasts. Fibroblasts were isolated and cultured from right atrial appendage samples obtained from patients during during cardiac surgery. Cells were then treated with bovine serum albumin (BSA) conjugated with DOPAL, N(6)‐Carboxymethyllysine (CML, an advanced glycation end product), and 4‐hydroxynonenal (HNE, a n6 polyunsaturated fatty acid‐derived aldehyde). Collagen type I and III were measured in the media via immunoblot. Collagen content in the media increased with CML‐, HNE‐ and DOPAL‐BSA (P<0.05), as compared with BSA alone (control). Surprisingly, treatment with DOPAL increased type I and type III collagen secretion by 11‐fold and 32‐fold, respectively, compared to vehicle‐treated cells (P<0.05), an effect that was >5‐fold greater than with either CML or HNE. These findings suggest that reactive aldehydes, particularly catecholaldehydes, may significantly contribute to fibrosis in the heart via increased collagen secretion. Further, they provide evidence that compounds with aldehyde‐scavenging capacity may have therapeutic value in mitigating cardiac fibrosis.Support or Funding InformationR01HL122863‐01
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