Theranostics 2018; 8(4):1027-1041. doi:10.7150/thno.22414 This issue

Research Paper

Targeting ALDH2 for Therapeutic Interventions in Chronic Pain-Related Myocardial Ischemic Susceptibility

Chen Li1,2*, Wanqing Sun3*, Chunhu Gu4*, Zheng Yang1,2, Nanhu Quan5, Jingrun Yang2, Zhaoling Shi2, Lu Yu6✉, Heng Ma1,2✉

1. Department of Pathophysiology, Fourth Military Medical University, Xi'an, 710032, China;
2. Department of Physiology, Fourth Military Medical University, Xi'an, 710032, China;
3. Fuwai Hospital, National Center of Cardiovascular Diseases, Beijing 100037, China;
4. Department of Cardiovascular Surgery, Xijing Hospital, Fourth Military Medical University, Xi'an, 710032, China;
5. Cardiovascular center, First Affiliated Hospital of Jilin University, Changchun, 130000, China;
6. Department of Pathology, Xijing Hospital, Fourth Military Medical University, Xi'an, 710032, China.
* These authors contributed equally to this work

This is an open access article distributed under the terms of the Creative Commons Attribution (CC BY-NC) license ( See for full terms and conditions.
Li C, Sun W, Gu C, Yang Z, Quan N, Yang J, Shi Z, Yu L, Ma H. Targeting ALDH2 for Therapeutic Interventions in Chronic Pain-Related Myocardial Ischemic Susceptibility. Theranostics 2018; 8(4):1027-1041. doi:10.7150/thno.22414. Available from

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Graphic abstract

Clinical observations have demonstrated a link between chronic pain and increased ischemic heart disease mortality, but the mechanisms remain elusive. Reactive aldehydes have recently been confirmed as a new player in pain pathologies, while our previous study demonstrated that reactive aldehydes (4-HNE) induced carbonyl stress contributing to myocardial ischemic intolerance. The aim of this study was to explore whether chronic pain increases susceptibility to myocardial ischemia/reperfusion (MI/R) injury and to investigate the underlying mechanisms focusing on toxic aldehyde and carbonyl stress.

Methods: Chronic pain was induced by chronic compression of the dorsal root ganglion (CCD). After 2 weeks CCD, aldehyde dehydrogenase (ALDH2) KO or wild-type (WT) littermate mice were then subjected to in vivo MI/R.

Results: In CCD-WT mice, heightened nociception paralleled circulating aldehyde (4-HNE) accumulation and cardiac protein carbonylation. Mechanistically, CCD-induced 4-HNE overload provoked cardiac Sirtuin 1 (SIRT1) carbonylative inactivation and inhibited Liver kinase B1 (LKB1) - AMP-activated protein kinase (LKB1-AMPK) interaction, which resulted in exacerbated MI/R injury and higher mortality compared with non-CCD WT mice. ALDH2 deficiency further aggravated CCD-induced susceptibility to MI/R injury. Exogenous 4-HNE exposure in peripheral tissue mimicked chronic pain-induced aldehyde overload, elicited sustained allodynia and increased MI/R injury. However, cardiac-specific ALDH2 upregulation by AAV9-cTNT-mediated gene delivery significantly ameliorated chronic pain-induced SIRT1 carbonylative inactivation and decreased MI/R injury (minor infarct size, less apoptosis, and improved cardiac function).

Conclusion: Collectively, chronic pain-enhanced carbonyl stress promotes myocardial ischemic intolerance by SIRT1 carbonylative inactivation and impairment of LKB1-AMPK interaction. ALDH2 activation and prevention of protein carbonylation may be a potential therapeutic target for myocardial ischemic vulnerability in chronic pain patients. Our results newly provided overlapping cellular mechanisms of chronic pain and myocardial dysfunction interplay.

Keywords: chronic pain, myocardial ischemic intolerance, ALDH2, 4-HNE, carbonylation.