PURPOSE Myocardial infarction (MI) triggers a local inflammatory response which orchestrates cardiac repair and contributes to concurrent neuroinflammation. Angiotensin-converting enzyme (ACE) inhibitor therapy not only attenuates cardiac remodeling by interfering with the neurohumoral system, but also influences acute leukocyte mobilization from hematopoietic reservoirs. Here, we seek to dissect the anti-inflammatory and anti-remodeling contributions of ACE inhibitors to the benefit of heart and brain outcomes after MI. METHODS C57BL/6 mice underwent permanent coronary artery ligation (n = 41) or sham surgery (n = 9). Subgroups received ACE inhibitor enalapril (20 mg/kg, oral) either early (anti-inflammatory strategy; 10 days treatment beginning 3 days prior to surgery; n = 9) or delayed (anti-remodeling; continuous from 7 days post-MI; n = 16), or no therapy (n = 16). Cardiac and neuroinflammation were serially investigated using whole-body macrophage- and microglia-targeted translocator protein (TSPO) PET at 3 days, 7 days, and 8 weeks. In vivo PET signal was validated by autoradiography and histopathology. RESULTS Myocardial infarction evoked higher TSPO signal in the infarct region at 3 days and 7 days compared with sham (p < 0.001), with concurrent elevation in brain TSPO signal (+ 18%, p = 0.005). At 8 weeks after MI, remote myocardium TSPO signal was increased, consistent with mitochondrial stress, and corresponding to recurrent neuroinflammation. Early enalapril treatment lowered the acute TSPO signal in the heart and brain by 55% (p < 0.001) and 14% (p = 0.045), respectively. The acute infarct signal predicted late functional outcome (r = 0.418, p = 0.038). Delayed enalapril treatment reduced chronic myocardial TSPO signal, consistent with alleviated mitochondrial stress. Early enalapril therapy tended to lower TSPO signal in the failing myocardium at 8 weeks after MI (p = 0.090) without an effect on chronic neuroinflammation. CONCLUSIONS Whole-body TSPO PET identifies myocardial macrophage infiltration and neuroinflammation after MI, and altered cardiomyocyte mitochondrial density in chronic heart failure. Improved chronic cardiac outcome by enalapril treatment derives partially from acute anti-inflammatory activity with complementary benefits in later stages. Whereas early ACE inhibitor therapy lowers acute neuroinflammation, chronic alleviation is not achieved by early or delayed ACE inhibitor therapy, suggesting a more complex mechanism underlying recurrent neuroinflammation in ischemic heart failure.

中文翻译：

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心肌梗塞后早期进行血管紧张素转换酶抑制剂治疗可减轻急性心脏和神经炎症，而对慢性神经炎症没有影响。

目的心肌梗塞（MI）触发局部炎症反应，协调心脏修复并促进并发神经炎症。血管紧张素转换酶（ACE）抑制剂疗法不仅通过干扰神经体液系统来减弱心脏重塑，而且还会影响从造血系统中急性白细胞的动员。在这里，我们试图剖析ACE抑制剂对MI后心脏和大脑结局的益处的抗炎和抗重塑作用。方法对C57BL / 6小鼠进行永久性冠状动脉结扎术（n = 41）或假手术（n = 9）。亚组或早（抗炎策略；手术前3天开始治疗10天； n = 9）或延迟（抗重塑； MI后7天开始连续；抗炎策略；连续；从MI开始7天开始；连续）接受ACE抑制剂依那普利（20 mg / kg，口服）。 n = 16），或不进行任何治疗（n = 16）。在3天，7天和8周时，使用全身巨噬细胞和小胶质靶向性转运蛋白（TSPO）PET对心脏和神经炎症进行了系列研究。通过放射自显影和组织病理学证实了体内PET信号。结果与假手术相比，心肌梗死在第3天和第7天诱发了更高的TSPO信号（p <0.001），同时脑TSPO信号升高（+ 18％，p = 0.005）。MI后8周，远端心肌TSPO信号增加，与线粒体压力一致，并对应于神经炎反复发作。早期的依那普利治疗可使心脏和大脑中的急性TSPO信号分别降低55％（p <0.001）和14％（p = 0.045）。急性梗塞信号可预测晚期功能预后（r = 0.418，p = 0.038）。依那普利的延迟治疗降低了慢性心肌TSPO信号，与减轻的线粒体压力一致。早期的依那普利治疗倾向于在MI后8周降低衰竭的心肌中的TSPO信号（p = 0.090），而不影响慢性神经炎症。结论全身TSPO PET可确定MI后心肌巨噬细胞浸润和神经炎症，并在慢性心力衰竭中改变心肌线粒体密度。依那普利治疗改善的慢性心脏结局部分源自急性抗炎活性，在后期具有互补的益处。早期的ACE抑制剂治疗可降低急性神经炎症，而早期或延迟的ACE抑制剂治疗无法实现慢性缓解，