Depression is associated with increased morbidity and mortality following acute myocardial infarction (AMI), but the underlying mechanisms of this link are not well understood. Haykin et al show that 2 weeks of daily chemogenetic stimulation of dopamine (DA) neurons in the ventral tegmental area (VTA) — part of the brain’s reward system, which is altered in depression — following AMI in mice reversed myocardial damage, increased myocardial vascularization, restored cardiac performance, and resulted in reduced fibrosis (scarring) of heart tissue compared with control AMI mice. It also resulted in lower plasma IL-7 and TGFβ levels, and a higher CD4:CD8 ratio, fewer CD68+ myeloid cells and increased expressed of complement factor C3 (which has been implicated in tissue recovery) in cardiac tissue 4 days after AMI. Of various C3-producing tissues, only the liver showed increased C3 mRNA expression in these mice. The authors identified a neural pathway from VTA DA neurons to the liver. Stimulation of VTA DA neurons decreased liver norepinephrine levels, and peripheral norepinephrine injection decreased liver C3 mRNA levels, suggesting that a sympathetic VTA–liver neural pathway may stimulate hepatic C3 production. Interestingly, a C3-cleavage inhibitor administered concurrently with stimulation of VTA DA neurons reduced many of the beneficial effects of the stimulation in AMI mice. Plasma or liver protein extracts from AMI mice that had received VTA DA-neuron stimulation promoted in vitro blood-vessel formation more than plasma or extracts from control AMI mice, and this difference was also abolished by a C3-cleavage inhibitor. Together, these findings support a model in which activation of VTA DA neurons reduces adrenergic input to the liver, resulting in increased C3 production, which in turn promotes the formation of new cardiac blood vessels. Future studies may assess whether this intriguing mechanism could be recruited through behavioural or other non-invasive approaches in patients with AMI.
Original reference: Nat. Cardiovasc. Res. 3, 841–856 (2024)
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