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)

抑郁症与急性心肌梗死（AMI）后发病率和死亡率增加有关，但这种联系的潜在机制尚不清楚。 Haykin 等人表明，在小鼠发生 AMI 后，对腹侧被盖区 (VTA) 的多巴胺 (DA) 神经元进行两周的化学遗传学刺激（VTA 是大脑奖赏系统的一部分，在抑郁状态下会发生改变），可逆转心肌损伤，增加心肌血管化与对照 AMI 小鼠相比，恢复了心脏功能，并减少了心脏组织的纤维化（疤痕）。它还导致 AMI 后 4 天心脏组织中血浆 IL-7 和 TGFβ 水平降低、CD4:CD8 比率升高、CD68 ⁺骨髓细胞减少以及补体因子 C3（与组织恢复有关）表达增加。在这些小鼠的各种产生 C3 的组织中，只有肝脏显示出C3 mRNA 表达增加。作者确定了一条从 VTA DA 神经元到肝脏的神经通路。刺激 VTA DA 神经元会降低肝脏去甲肾上腺素水平，而外周去甲肾上腺素注射会降低肝脏C3 mRNA 水平，表明交感 VTA-肝脏神经通路可能会刺激肝脏 C3 的产生。有趣的是，在刺激 VTA DA 神经元的同时给予 C3 裂解抑制剂，会降低 AMI 小鼠中刺激的许多有益效果。接受 VTA DA 神经元刺激的 AMI 小鼠的血浆或肝脏蛋白提取物比对照 AMI 小鼠的血浆或提取物更能促进体外血管形成，并且这种差异也被 C3 裂解抑制剂消除。 总之，这些发现支持了一个模型，其中 VTA DA 神经元的激活减少了肝脏的肾上腺素能输入，导致 C3 产量增加，进而促进新心血管的形成。未来的研究可能会评估是否可以通过行为或其他非侵入性方法在 AMI 患者中招募这种有趣的机制。

原始参考文献： Nat。资源。 3、841–856 (2024)