Abstract
Monoamine oxidase (MAO) is rapidly gaining appreciation for its pathophysiologic role in cardiac injury and failure. Oxidative deamination of norepinephrine by MAO generates H2O2 and the catecholaldehyde 3,4-dihydroxyphenylglycolaldehyde (DOPEGAL), the latter of which is a highly potent and reactive electrophile that has been linked to cardiotoxicity. However, many questions remain as to whether catecholaldehydes regulate basic physiological processes in the myocardium and the pathways involved. Here, we examined the role of MAO-derived oxidative metabolites in mediating the activation of cardiac fibroblasts in response to norepinephrine. In neonatal murine cardiac fibroblasts, norepinephrine increased reactive oxygen species (ROS), accumulation of catechol-modified protein adducts, expression and secretion of collagens I/III, and other markers of profibrotic activation including STAT3 phosphorylation. These effects were attenuated with MAO inhibitors, the aldehyde-scavenging dipeptide l-carnosine, and FPS-ZM1, an antagonist for the receptor for advanced glycation endproducts (RAGE). Interestingly, treatment of cardiac fibroblasts with a low dose (1 μM) of DOPEGAL-modified albumin phenocopied many of the effects of norepinephrine and also induced an increase in RAGE expression. Higher doses (>10 μM) of DOPEGAL-modified albumin were determined to be toxic to cardiac fibroblasts in a RAGE-dependent manner, which was mitigated by l-carnosine. Collectively, these findings suggest that norepinephrine may influence extracellular matrix remodeling via an adrenergic-independent redox pathway in cardiac fibroblasts involving the MAO-mediated generation of ROS, catecholaldehydes, and RAGE. Furthermore, since elevations in the catecholaminergic tone and oxidative stress in heart disease are linked with cardiac fibrosis, this study illustrates novel drug targets that could potentially mitigate this serious disorder.
Highlights
Myocardial fibrosis, the pathological accumulation of collagen in the myocardium, is the result of an excessive wound-healing response facilitated by fibroblasts becoming activated in response to neurohumoral stimuli
Exposure to NE substantially increased catechol adduct levels in primary murine cardiac fibroblasts (CFs), which were attenuated with monoamine oxidase inhibitors (MAOIs) clorgiline and selegiline (Figure 1B)
A new paradigm of catecholamine pathogenicity in the heart has recently emerged, which is completely independent of canonical adrenergic signaling but rather dependent on the Monoamine oxidase (MAO)-catalyzed oxidative metabolites formed from intracellular catecholamine metabolism
Summary
Myocardial fibrosis, the pathological accumulation of collagen in the myocardium, is the result of an excessive wound-healing response facilitated by fibroblasts becoming activated (i.e., myofibroblasts) in response to neurohumoral stimuli. The transition of resident cardiac fibroblasts to a myofibroblast phenotype is marked by accelerated proliferation and increases in collagen deposition, expression of α smooth muscle actin (αSMA), and expression of proinflammatory chemo/cytokines.[1] While it can be important in maintaining the integrity of an injured myocardium, extracellular matrix expansion contributes to the pathogenesis of heart failure and arrhythmia by interfering with normal elasticity and electrical conductivity in myocardial tissue.[2] Myocardial fibrosis is known to be associated with common metabolic conditions such as diabetes and obesity[3,4] and is a prominent feature in the etiology of most cardiomyopathies.[1] The molecular and cellular mechanisms underlying cardiac fibrosis are only partially understood, reflected in the current paucity of therapies targeting this disorder. MAO deaminates NE to produce ammonia, hydrogen peroxide, and the reactive aldehyde 3,4-dihydroxyphenylglycolaldehyde (DOPEGAL). This biogenic “catecholaldehyde” is substantially more cytotoxic and reactive than its parent catecholamines or any Received: July 27, 2021 Published: October 5, 2021
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