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Int J Biol Sci 2024; 20(6):2072-2091. doi:10.7150/ijbs.89883 This issue Cite

Research Paper

Optogenetic Stimulation of the Cardiac Vagus Nerve to Promote Heart Regenerative Repair after Myocardial Infarction

Yuan Han^1,3*, Xiaomin Wei^1,2,3*, Guojun Chen^1,3*, Enge Shao^1,3, Yilin Zhou^1,3, Yuqing Li⁴, Zhiwen Xiao^1,3, Xiaoran Shi^1,3, Hao Zheng^1,3, Senlin Huang^1,3, Yanmei Chen^1,3, Yanbing Wang^1,3, Yeshen Zhang⁵, Yulin Liao^1,3, Wangjun Liao⁶, Jianping Bin^1,3✉, Yuegang Wang^1,3✉, Xinzhong Li^1,3✉

1. Department of Cardiology, State Key Laboratory of Organ Failure Research, Nanfang Hospital, Southern Medical University, Guangzhou, China.
2. The Sixth Affiliated Hospital, School of Medicine, South China University of Technology, Foshan, China.
3. Guangdong Provincial Key Laboratory of Cardiac Function and Microcirculation.
4. Department of Nosocomial Infection Administration, Zhujiang Hospital, Southern Medical University, Guangzhou, China.
5. Department of Cardiology, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, China.
6. Department of Oncology, Nanfang Hospital, Southern Medical University, Guangzhou, China.
*Yuan Han, Xiaomin Wei and Guojun Chen contributed equally to this work.

✉ Corresponding authors: Xinzhong Li, Department of Cardiology, State Key Laboratory of Organ Failure Research, Nanfang Hospital, Southern Medical University, 1838 North Guangzhou Avenue, Guangzhou 510515, China. Mobile: (+86)13268265165, E-mail: lxz07111309com; Yuegang Wang, Department of Cardiology, Nanfang Hospital, Southern Medical University. E-mail: wyg06edu.cn. Jianping Bin, Department of Cardiology, Nanfang Hospital, Southern Medical University. E-mail: jianpingbincom or jianpingbincom. More

Abstract

Background: It had been shown that selective cardiac vagal activation holds great potential for heart regeneration. Optogenetics has clinical translation potential as a novel means of modulating targeted neurons. This study aimed to investigate whether cardiac vagal activation via optogenetics could improve heart regenerative repair after myocardial infarction (MI) and to identify the underlying mechanism.

Methods: We used an adeno-associated virus (AAV) as the vector to deliver ChR2, a light-sensitive protein, to the left nodose ganglion (LNG). To assess the effects of the cardiac vagus nerve on cardiomyocyte (CM) proliferation and myocardial regeneration in vivo, the light-emitting diode illumination (470 nm) was applied for optogenetic stimulation to perform the gain-of-function experiment and the vagotomy was used as a loss-of-function assay. Finally, sequencing data and molecular biology experiments were analyzed to determine the possible mechanisms by which the cardiac vagus nerve affects myocardial regenerative repair after MI.

Results: Absence of cardiac surface vagus nerve after MI was more common in adult hearts with low proliferative capacity, causing a poor prognosis. Gain- and loss-of-function experiments further demonstrated that optogenetic stimulation of the cardiac vagus nerve positively regulated cardiomyocyte (CM) proliferation and myocardial regeneration in vivo. More importantly, optogenetic stimulation attenuated ventricular remodeling and improved cardiac function after MI. Further analysis of sequencing results and flow cytometry revealed that cardiac vagal stimulation activated the IL-10/STAT3 pathway and promoted the polarization of cardiac macrophages to the M2 type, resulting in beneficial cardiac regenerative repair after MI.

Conclusions: Targeting the cardiac vagus nerve by optogenetic stimulation induced macrophage M2 polarization by activating the IL-10/STAT3 signaling pathway, which obviously optimized the regenerative microenvironment and then improved cardiac function after MI.

Keywords: Optogenetic stimulation, cardiac vagal, heart regeneration, myocardial infarction

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