Abstract 421: Norepinephrine Catabolism Drives Cardiac Fibroblast Activation via Monoamine Oxidase Activity and Rage/β-adrenergic Signaling

Abstract

The mitochondrial enzyme monoamine oxidase A (MAO-A) plays an increasingly appreciated role in cardiac remodeling induced by diabetes and ischemic injury. Oxidative deamination of norepinephrine (NE) by MAO-A generates 3,4-dihydroxyphenylglycolaldehyde (DOPEGAL) and H 2 O 2 . Isolation and quantification of catechol-modified proteins from cardiac fibroblast lysate using an aminophenylboronic acid resin showed an MAO-dependent accumulation of catechol adducts in NE-treated cells (P<0.05). Our lab has previously observed increased expression and activity of MAO in myocardium of diabetes patients compared with age-matched nondiabetic patients. Moreover, preliminary data suggest that catecholaldehydes and other biogenic aldehydes might contribute to the pathogenesis of cardiac fibrosis in diabetic cardiomyopathy via pro-fibrotic signaling mechanisms. We hypothesize that NE activates fibroblasts by both canonical pathways (i.e, adrenergic receptors) and by monoamine oxidase-mediated catabolism and activation of the receptor for advanced glycation endproducts (RAGE). Treatment of cardiac fibroblasts with NE (1 μM) resulted in accelerated proliferation, enhanced collagen I & III secretion, robust increases in mitochondrial and total cellular ROS, and upregulated pro-fibrotic gene expression. These effects were abrogated by co-administration of RAGE antagonist FPS-ZM1, MAO inhibitors, β-blocker propranolol, and the aldehyde scavenger carnosine (P<0.05). These findings suggest that NE (and other catecholamines) may influence extracellular matrix remodeling via multiple pathways, including adrenergic and also RAGE, via MAO-mediated catabolism.