Increased sympathetic outflow induced by emotional stress aggravates myocardial ischemia-reperfusion injury via activation of TLR7/MyD88/IRF5 signaling pathway.

Abstract

Emotional stress substantially increases the risk of ischemic cardiovascular diseases. Previous study indicates that sympathetic outflow is increased under emotional stress. We aim to investigate the role of increased sympathetic outflow induced by emotional stress in myocardial ischemia-reperfusion (I/R) injury, and explore the underlying mechanisms. We used Designer Receptors Exclusively Activated by Designer Drugs technique to activate the ventromedial hypothalamus (VMH), a critical emotion-related nucleus. The results revealed that emotional stress stimulated by VMH activation increased sympathetic outflow, enhanced blood pressure, aggravated myocardial I/R injury, and exacerbated infarct size. The RNA-seq and molecular detection demonstrated that toll-like receptor 7 (TLR7), myeloid differentiation factor 88 (MyD88), interferon regulatory factor 5 (IRF5), and downstream inflammatory markers in cardiomyocytes were significantly upregulated. Emotional stress-induced sympathetic outflow further exacerbated the disorder of the TLR7/MyD88/IRF5 inflammatory signaling pathway. While inhibition of the signaling pathway partially alleviated myocardial I/R injury aggravated by emotional stress-induced sympathetic outflow. Increased sympathetic outflow induced by emotional stress activates TLR7/MyD88/IRF5 signaling pathway, ultimately aggravating I/R injury.