A Catecholaldehyde Metabolite of Norepinephrine Induces Myofibroblast Activation and Toxicity via the Receptor for Advanced Glycation Endproducts: Mitigating Role of l-Carnosine

Abstract

Monoamine oxidase (MAO) is rapidly gaining appreciation for its pathophysiologic role in cardiac injury and failure. Oxidative deamination of norepinephrine by MAO generates H 2 O 2 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.

Mesenchymal Stem Cell Therapy in Diabetic Cardiomyopathy

“…Furthermore, AGE can alter SOD expression and impact the expression of proteins related to ECM remodeling [ 21 ]. Thus, the increase in ROS, the accumulation of catechol-modified proteins, the expression and secretion of type I and type III collagen and pro-fibrotic activation markers (such as STAT3) explain the occurrence of extracellular matrix remodeling [ 36 ]. Increased AGE has also been implicated in fibroblast activation and proliferation in DM [ 37 ].…”

Iron scavenging and suppression of collagen cross-linking underlie antifibrotic effects of carnosine in the heart with obesity

“…The aldehyde mixture included 4-HNE (lipid-derived aldehyde), 3,4-dihydroxyphenylacetaldehyde (DOPAL) and 3,4-dihydroxyphenylglycolaldehyde (DOPEGAL). The latter are dopamine and norepinephrine metabolites, respectively, which we have previously shown are biogenic aldehydes formed in heart and are increased in myocardial tissues from patients with T2 diabetes ( Monroe and Anderson, 2021 ; Nelson et al, 2021 ). We found that collagen cross-linking was stimulated by these aldehydes in the absence ( p = 0.0545) and presence of glucose, as indicated by higher shear modulus of the suspension ( Figure 3D ).…”

Cardiac MAO-A inhibition protects against catecholamine-induced ventricular arrhythmias via enhanced diastolic calcium control

“…In addition, CaMKII can also be activated by oxidative stress and contribute to arrhythmias 60 . Previous work from our group and others have shown that cardiac MAO-A are robust generators of H2O2 and reactive catecholaldehydes 12,61 , the latter of which causes disruptions in mitochondrial oxidative phosphorylation (OxPHOS) 62 , and stimulates proinflammatory/pro-fibrotic signaling in the myocardium 63 . A decrease in oxidative stress in cMAO-A def hearts following catecholaminergic overload would thus predictably avoid the overaction of CaMKII and other adverse effects, all of which could contribute to the reduced arrhythmogenesis found in the cMAO-A def mice.…”