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Reactive aldehydes contribute to pain pathologies and cardiac injury, suggesting that aldehyde dehydrogenase (ALDH2), which detoxifies aldehydes, may regulate chronic pain related MI/R injury. However, whether chronic pain enhances susceptibility to myocardial ischemia/reperfusion (MI/R) and the underlying mechanisms remain unknown.
In this study, chronic neuropathic pain was induced by chronic compression of the dorsal root ganglion (CCD). CCD for 2 weeks, ALDH2 KO or wild-type (WT) littermates were subjected to in vivo MI/R.
CCD-WT mice exhibited heightened nociception than pain free mice and nociception tightly correlated with circulating aldehyde (4-HNE) accumulation and cardiac protein carbonylation. CCD induced 4-HNE overload provoked cardiac SIRT1 carbonylative inactivation and impairment the cardioprotection of LKB1-mediated AMPK activation during MI/R, which resulting in enhanced MI/R injury and higher mortality compare with pain free WT mice. In comparison to WT, chronic neuropathic pain enhanced susceptibility to MI/R injury was further exacerbated by ALDH2 deficiency in which associated with more impaired SIRT1-LKB1-AMPK signaling. Further, peripheral injection of 4-HNE induced a sustained allodynia, and increased circulating aldehyde load to the same degree as that seen in CCD-WT mice. The 4-HNE exposure can simulate cardiac SIRT1 carbonylative inactivation and sensitization to MI/R injury, which was observed in CCD-WT mice. However, treatment of CCD-WT mice with ALDH2-selective activator (Alda-1) significantly reduced chronic neuropathic pain-induced SIRT1 carbonylative inactivation and decreased MI/R injury (minor infarct size, less apoptosis, and elevated cardiac function) likely as a result of prevented aldehyde overload and carbonyl stress.
These results strongly suggest that elevated reactive aldehyde concentration, like that observed in the presence of chronic pain, may render cardiomyocytes more susceptible to I/R injury by SIRT1 carbonylative inactivation and impairment the cardioprotection of LKB1-mediated AMPK activation. ALDH2 activation blocked reactive aldehyde overproduction induced carbonyl stress and attenuated ischemic vulnerability in chronic pain individual.