Recovery of the interstitial cells of Cajal (ICCs) during post-operative ileus (POI) is important for the restoration of gastrointestinal (GI) motility. Acupuncture can protect ICCs, but the underlying mechanisms remain unclear. In this study, we investigated whether miR-222, c-kit and endothelial nitric oxide synthase (eNOS) are involved in the putative effects of acupuncture on ICC recovery.
Methods:
A POI model was established in Sprague-Dawley rats by colo-colic anastomosis, and then acupuncture was performed at bilateral ST36, SP6 and LR3 once daily for 3 consecutive days. C-kit protein expression in the colonic tissue adjacent to the incision site was determined by immunohistochemistry and Western blotting. mRNA levels of c-kit, eNOS and miR-222 were measured by real-time polymerase chain reaction (RT-PCR).
Results:
The levels of c-kit mRNA/protein and eNOS mRNA decreased, while miR-222 increased in the colonic tissues of POI model rats. Acupuncture treatment improved GI motility, inhibited the up-regulation of miR-222 and blocked the down-regulation of c-kit mRNA/protein and eNOS mRNA. The levels of miR-222 and c-kit were negatively correlated.
Conclusion:
Acupuncture at ST36, SP6 and LR3 facilitates ICC recovery and improves post-operative GI motility in part through regulation of miR-222, c-kit and eNOS.
TorihashiSNishiKTokutomiY, et al. Blockade of kit signaling induces transdifferentiation of interstitial cells of Cajal to a smooth muscle phenotype. Gastroenterology1999; 117: 140–148.
2.
RenHHanJLiZ, et al. Stem cell factor/Kit signal insufficiency contributes to hypoxia-induced intestinal motility dysfunctions in neonatal mice. Dig Dis Sci2017; 62: 1193–1203.
3.
ChenBZhuSDuL, et al. Reduced interstitial cells of Cajal and increased intraepithelial lymphocytes are associated with development of small intestinal bacterial overgrowth in post-infectious IBS mouse model. Scand J Gastroenterol2017; 52: 1065–1071.
4.
GfroererSRolleU.Interstitial cells of Cajal in the normal human gut and in Hirschsprung disease. Pediatr Surg Int2013; 29: 889–897.
5.
FeldsteinAEMillerSMEl-YoussefM, et al. Chronic intestinal pseudoobstruction associated with altered interstitial cells of Cajal networks. J Pediatr Gastroenterol Nutr2003; 36: 492–497.
6.
ZhengKZhaoJJiangC, et al. Relationship between miR-128 expression and abnormal colonic interstitial cells of Cajal in patients with colonic slow transit constipation. Zhonghua Shi Yan Wai Ke Za Zhi2012; 29: 1768–1770.
7.
MeiFYuBMaH, et al. Interstitial cells of Cajal could regenerate and restore their normal distribution after disrupted by intestinal transection and anastomosis in the adult guinea pigs. Virchows Arch2006; 449: 348–357.
8.
YanagidaHYanaseHSandersKM, et al. Intestinal surgical resection disrupts electrical rhythmicity, neural responses, and interstitial cell networks. Gastroenterology2004; 127: 1748–1759.
9.
YanagidaHSandersKMWardSM.Inactivation of inducible nitric oxide synthase protects intestinal pacemaker cells from postoperative damage. J Physiol2007; 582: 755–765.
10.
DengJYangSYuanQ, et al. Acupuncture ameliorates postoperative ileus via IL-6-miR-19a-KIT axis to protect interstitial cells of Cajal. Am J Chin Med2017; 45: 737–755.
11.
DengJYuanQWangM, et al. Effects of acupuncture on NO and NOS in restoration environment of interstitial cells of Cajal after colonic anastomosis. Zhongguo Zhen Jiu2015; 35: 1033–1038.
12.
PengMFLiKWangC, et al. Therapeutic effect and mechanism of electroacupuncture at Zusanli on plasticity of interstitial cells of Cajal: a study of rat ileum. BMC Complement Altern Med2014; 14: 186.
13.
EvangelistaAMDeschampsAMLiuD, et al. miR-222 contributes to sex-dimorphic cardiac eNOS expression via ets-1. Physiol Genomics2013; 45: 493–498.
14.
VannucchiMGCorsaniLBaniD, et al. Myenteric neurons and interstitial cells of Cajal of mouse colon express several nitric oxide synthase isoforms. Neurosci Lett2002; 326: 191–195.
15.
OrdögTWardSMSandersKM.Interstitial cells of Cajal generate electrical slow waves in the murine stomach. J Physiol1999; 518: 257–269.
16.
GaoHSuZWuM, et al. Expression and significance of miR-125 in Hirschsprung’s disease. Zhonghua Xiao Er Wai Ke Za Zhi2011; 32: 158–160.
GitsCMvan KuijkPFJonkersMB, et al. MiR-17–92 and miR-221/222 cluster members target KIT and ETV1 in human gastrointestinal stromal tumours. Br J Cancer2013; 109: 1625–1635.
19.
PolisenoLTuccoliAMarianiL, et al. MicroRNAs modulate the angiogenic properties of HUVECs. Blood2006; 108: 3068–3071.
20.
FelliNFontanaLPelosiE, et al. MicroRNAs 221 and 222 inhibit normal erythropoiesis and erythroleukemic cell growth via kit receptor down-modulation. Proc Natl Acad Sci USA2005; 102: 18081–18086.
21.
VelickovicKMarkelicMGolicI, et al. Long-term dietary L-arginine supplementation increases endothelial nitric oxide synthase and vasoactive intestinal peptide immunoexpression in rat small intestine. Eur J Nutr2014; 53: 813–821.
22.
ChoiKMGibbonsSJRoederJL, et al. Regulation of interstitial cells of Cajal in the mouse gastric body by neuronal nitric oxide. Neurogastroenterol Motil2007; 19: 585–595.
23.
DingSSHongSHWangC, et al. Acupuncture modulates the neuroendocrine-immune network. QJM2014; 107: 341–345.
24.
LiuWWuJHuangJ, et al. Electroacupuncture regulates hippocampal synaptic plasticity via miR-134-mediated LIMK1 function in rats with ischemic stroke. Neural Plast2017; 2017: 9545646.
25.
LiuWWangXZhengY, et al. Electroacupuncture inhibits inflammatory injury by targeting the miR-9-mediated NF-κB signaling pathway following ischemic stroke. Mol Med Rep2016; 13: 1618–1626.
26.
ZhaoHYaoRCaoX, et al. Neuroimmune modulation following traumatic stress in rats evidence for an immunoregulatory cascade mediated by c-Src, miRNA222 and PAK1. J Neuroinflammation2011; 8: 159.
27.
DengJYuanQWangM, et al. Effect of acupuncture on expression of receptor tyrosine kinase c-kit in interstitial cells of Cajal, carbon monoxide and heme oxygenase in colon tissue after colonic anastomosis in rats. Zhen Ci Yan Jiu2017; 42: 296–301.
28.
LaiMDengJWangM, et al. Effects of foot three-needle therapy on colonic cystathionine gamma-lyase and myeloperoxidase in postoperative rats. Guangzhou Zhong Yi Yao Da Xue Xue Bao2016; 33: 46–50.
29.
SiemensHJackstadtRKallerM, et al. Repression of c-Kit by p53 is mediated by miR-34 and is associated with reduced chemoresistance, migration and stemness. Oncotarget2013; 4: 1399–1415.
30.
KimWKParkMKimYK, et al. MicroRNA-494 downregulates KIT and inhibits gastrointestinal stromal tumor cell proliferation. Clin Cancer Res2011; 17: 7584–7594.
31.
LiuSWuLCPangJ, et al. Sp1/NFkappaB/HDAC/miR-29b regulatory network in KIT-driven myeloid leukemia. Cancer Cell2010; 17: 333–347.
