Norepinephrine metabolites enhance collagen cross-linking and induce a pro-fibrotic phenotype in cardiac fibroblasts via RAGE

Myocardial fibrosis is what’s colloquially referred to as “scarring” of the heart. Associated with common conditions such as diabetes, obesity, and hypertension, fibrosis directly gives rise to the deadliest heart conditions such as cardiac arrythmia (i.e. irregular heartbeat) and diastolic heart failure. Despite this incalculable impact on many American’s quality of life, there are currently no FDA-approved treatments for cardiac fibrosis and our understanding of the underpinnings of cardiac fibrosis remains incomplete. My dissertation provides new insight into the development of cardiac fibrosis in diabetes and could inform therapeutic strategies to fulfill an urgent clinical need.

The characteristic raised blood sugar of diabetes often alters the physiology and biochemistry of many of the body’s systems, including the cardiovascular and nervous systems. Nerves that connect the brain to the heart regulate heartbeat in part through catecholamines, a class of neurotransmitters that include adrenaline and norepinephrine. Catecholamines are metabolized by the enzyme monoamine oxidase (MAO) to produce a series of particularly reactive class of chemicals called “catecholaldehydes.” Their known toxicity and involvement in other inflammatory pathologies make catecholaldehydes an attractive avenue to explore in the context of cardiac fibrosis. The purpose of my dissertation project is to describe possible mechanisms linking cardiac MAO activity with fibrosis and structural remodeling, potentially equip drug researchers and clinicians with the understanding to go about treating it. Someday, MAO could prove to be an attractive druggable enzyme or catecholaldehydes could be targeted for scavenging in treatments for cardiac fibrosis.