Homovanillic acid improves anxiety by regulating F4/80+ microglia/macrophage in adult mice with neonatal cardiac injury.

The heart-brain axis is a significant contributor to morbidity and mortality following ischemic injury. Pathological and psychological changes in the heart can lead to anxiety, cognitive impairment, and brain injury. Cardiac injury releases a substantial number of metabolites into the peripheral circulation, which exacerbates brain damage and dysfunction. Homovanillic acid (HVA), a metabolite of dopamine (DA), plays a crucial role in behavioral symptoms. However, there are limited studies examining the effects of cardiac metabolites released from an injured heart on behavioral symptoms in human juveniles, particularly in those who have suffered from severe cardiovascular diseases since childhood in human models. To study the potential role of injured cardiac metabolites on human juveniles’ behaviors, we use neonatal mouse heart cryoinjury to verify the mechanisms of heart-brain interactions in our study. Here, downregulated cardiac heart HVA is enriched in neonatal mouse injured heart at day 7 after injury, and meanwhile HVA treatment changes the physiology of the body such as heart weight/body weight, brain weight/body weight and thymus weight/body weight in mouse juveniles with chronic mouse cardiac injury. Additionally, HVA administration mediates anxiety-like behavior in the same group. Microglia/macrophages contribute to brain development and functions, potentially influencing on human behaviors, which is associates with MCP-1 expression. Mechanistically, we identifies the number of F4/80+ microglia/macrophage in adult mice with neonatal cardiac injury increases in HVA treatment, while there is no difference in mRNA and protein expression levels of MCP-1 at day 42 after injury. Thus, HVA may be a potential target in clinical behavioral symptoms with cardiovascular diseases.