Kihara Minoru, Kaiya Hiroyuki, Hirai Yumi, Katayama Hidekazu, Terao Akira, Nishikawa Masazumi
Department of Marine Biology and Sciences, School of Biological Sciences, Tokai University, 5-1-1-1 Minamisawa, Minami-ku, Sapporo, 005-8601, Japan.
Department of Biochemistry, National Cerebral and Cardiovascular Center Research Institute, 6-1 Kishibe-shinmachi, Suita, 564-8565, Japan.
Peptides. 2021 Mar;137:170471. doi: 10.1016/j.peptides.2020.170471. Epub 2020 Dec 16.
We had reported that orally administered ghrelin-containing salmon stomach extract prevents doxorubicin (DOX)-induced cardiotoxicity. In this study, we investigated the binding affinity of salmon ghrelin to rat ghrelin receptor and the cardioprotective effects of subcutaneous (sc) injected synthetic salmon ghrelin in rats with DOX-induced acute heart failure in order to clarify the potential efficacy of salmon ghrelin. Intracellular calcium mobilization assay was performed on rat GHS-R1a-expressing CHO cells to reveal ghrelin activity. Rats were divided into five groups; the normal control (I), and toxic control (II) groups were given saline (sc, twice daily), and the salmon acyl-ghrelin (sAG) (III), salmon unacylated-ghrelin (sUAG) (IV), and rat acyl-ghrelin (rAG) (V) groups were given corresponding synthetic ghrelins (sc, twice daily), respectively. After seven days of treatment, DOX (20 mg/kg BW) or saline was administered to the corresponding groups by intraperitoneal injection. The toxic control group was the negative control group for the DOX-induced cardiotoxicity groups. While sAG displayed similar affinity to rAG upon application to GHS-R1a-expressing cells, and also decreased DOX-induced apoptosis and increased food intake, sUAG did not. Both sAG and rAG improved DOX-induced deterioration, showing anti-oxidative activity. The anti-oxidative activity of sAG might contribute to the protective effects on cardiomyocytes. The results also suggest that, similar to rAG, sAG is a potent protectant against DOX-induced cardiotoxicity and a potential functional component in orally administered ghrelin-containing salmon stomach extract, which prevented DOX-induced cardiotoxicity in our previous study.
我们曾报道，口服含胃饥饿素的鲑鱼胃提取物可预防阿霉素（DOX）诱导的心脏毒性。在本研究中，我们研究了鲑鱼胃饥饿素与大鼠胃饥饿素受体的结合亲和力，以及皮下注射合成鲑鱼胃饥饿素对DOX诱导的急性心力衰竭大鼠的心脏保护作用，以阐明鲑鱼胃饥饿素的潜在疗效。对表达大鼠GHS-R1a的CHO细胞进行细胞内钙动员试验，以揭示胃饥饿素活性。将大鼠分为五组；正常对照组（I）和毒性对照组（II）给予生理盐水（皮下注射，每日两次），鲑鱼酰化胃饥饿素（sAG）组（III）、鲑鱼去酰化胃饥饿素（sUAG）组（IV）和大鼠酰化胃饥饿素（rAG）组（V）分别给予相应的合成胃饥饿素（皮下注射，每日两次）。治疗7天后，通过腹腔注射向相应组给予DOX（20mg/kg体重）或生理盐水。毒性对照组是DOX诱导的心脏毒性组的阴性对照组。虽然sAG应用于表达GHS-R1a的细胞时显示出与rAG相似的亲和力，并且还减少了DOX诱导的细胞凋亡并增加了食物摄入量，但sUAG没有。sAG和rAG均改善了DOX诱导的恶化，表现出抗氧化活性。sAG的抗氧化活性可能有助于对心肌细胞的保护作用。结果还表明，与rAG相似，sAG是预防DOX诱导的心脏毒性的有效保护剂，并且是口服含胃饥饿素的鲑鱼胃提取物中的潜在功能成分，在我们之前的研究中该提取物预防了DOX诱导的心脏毒性。
