Chronic Neuropathic Pain Protects the Heart from Ischemia-Reperfusion Injury.

The prevalence of chronic pain increases with age. The pain occurrence in the elderly ranges from 25% to 80% in different countries. Ischemic heart disease is also prevailing in the aged people. Restored blood flow quickly rescues myocardium but also causes ischemia-reperfusion (IR) injury. Brief episodes of ischemia at a distant organ could reduce the myocardial reperfusion injury. This is called remote ischemic preconditioning (RIPC) cardioprotection. Several circulating factors and neurogenic signals contribute to the cardioprotection by RIPC. Preinfarction angina, a form of chest pain, is associated with significant cardioprotection in myocardial infarction patients. Activation of peripheral nociception also induces cardioprotection against IR injury via neurogenic pathway. It is possible that angina also induces nociceptive signal pathway to provide cardioprotection. It is unclear whether pre-existing chronic pain will also have a cardioprotection effect. We recently reported chronic neuropathic pain attenuates cardiac IR injury in mice. ERK activation in anterior nucleus of paraventricular thalamus (PVA) is required for this remote cardioprotection. Direct activation of PVA neurons also provides cardioprotection against cardiac IR injury. Chronic neuropathic pain-induced cardioprotection requires activation of parasympathetic nerves. This review summarizes the potential interaction of chronic pain and cardiac IR injury.

Author Correction: Cardioprotection induced in a mouse model of neuropathic pain via anterior nucleus of paraventricular thalamus.

The original version of this Article contained an error in the affiliation of the second author, Ya-Ting Chang. The correct affiliations for Ya-Ting Chang are Institute of Biomedical Sciences, Academia Sinica, Taipei, 115, Taiwan and International Graduate Program in Molecular Medicine, National Yang-Ming University and Academia Sinica, Taipei 115, Taiwan.

Cardioprotection induced in a mouse model of neuropathic pain via anterior nucleus of paraventricular thalamus.

Myocardial infarction is the leading cause of death worldwide. Restoration of blood flow rescues myocardium but also causes ischemia-reperfusion injury. Here, we show that in a mouse model of chronic neuropathic pain, ischemia-reperfusion injury following myocardial infarction is reduced, and this cardioprotection is induced via an anterior nucleus of paraventricular thalamus (PVA)-dependent parasympathetic pathway. Pharmacological inhibition of extracellular signal-regulated kinase activation in the PVA abolishes neuropathic pain-induced cardioprotection, whereas activation of PVA neurons pharmacologically, or optogenetic stimulation, is sufficient to induce cardioprotection. Furthermore, neuropathic injury and optogenetic stimulation of PVA neurons reduce the heart rate. These results suggest that the parasympathetic nerve is responsible for this unexpected cardioprotective effect of chronic neuropathic pain in mice.Various forms of preconditioning can prevent ischemic-reperfusion injury after myocardial infarction. Here, the authors show that in mice, the presence of chronic neuropathic pain can have a cardioprotective effect, and that this is dependent on neural activation in the paraventricular thalamus.

Overexpression of ADP-ribosylation factor 1 in human gastric carcinoma and its clinicopathological significance.

Gastric cancer is the sixth leading cause of cancer-related death in Taiwan, and the identification of related factors is essential to increase patient survival. ADP-ribosylation factor 1 (ARF1) was initially identified using 2-D electrophoresis combined with MALDI-time-of-flight mass spectrometry. ADP-ribosylation factor 1 belongs to the Ras superfamily or GTP-binding protein family and has been shown to enhance cell proliferation. In the current study, we evaluated the potential of ARF1 as a biomarker for gastric cancer detection. ADP-ribosylation factor 1 mRNA was upregulated in tumor tissues (compared with adjacent non-tumor tissues, n = 55) in approximately 67.2% of gastric cancer patients. Expression of ARF1 protein was additionally observed using Western blot and immunohistochemistry (IHC) analyses. The clinicopathological correlations of ARF1 were further evaluated. Elevated ARF1 expression was strongly correlated with lymph node metastasis (P = 0.008), serosal invasion (P = 0.046), lymphatic invasion (P = 0.035), and pathological staging (P = 0.010). Moreover, the 5-year survival rate for the lower ARF1 expression group (n = 50; IHC score < 90) was higher than that of the higher expression group (n = 60; IHC score ≥ 90) (P = 0.0228, log-rank test). To establish the specific function of ARF1 in human gastric cancer, isogenic ARF1-overexpressing cell lines were prepared. Our results showed that ARF1-overexpressing clones display enhanced cell proliferation, migration, and invasion. Furthermore, ARF1-overexpression might contribute to poor prognosis of patients. These findings collectively support the utility of ARF1 as a novel prognostic marker for gastric cancer and its role in cell invasion.