title: Long noncoding RNA H19 mediates melatonin inhibition of premature senescence of c-kit(+) cardiac progenitor cells by promoting miR-675.
abstract: Melatonin, a hormone secreted by the pineal gland, possesses multiple biological activities such as antitumor, antioxidant, and anti-ischemia. C-kit(+) cardiac progenitor cells (CPCs) have emerged as a promising tool for the treatment of heart diseases. However, the senescence of CPCs due to pathological stimuli leads to the decline of CPCs' functions and regenerative potential. This study was conducted to demonstrate whether melatonin antagonizes the senescence of CPCs in response to oxidative stress. Here, we found that the melatonin treatment markedly inhibited the senescent characteristics of CPCs after exposed to sublethal concentration of H2 O2 , including the increase in senescence-associated β-galactosidase (SA-β-gal)-positive CPCs, senescence-associated heterochromatin loci (SAHF), secretory IL-6 level, and the upregulation of p53 and p21 proteins. Senescence-associated proliferation reduction was also attenuated by melatonin in CPCs. Luzindole, the melatonin membrane receptor blocker, may block the melatonin-mediated suppression of premature senescence in CPCs. Interestingly, we found that long noncoding RNA H19 and its derived miR-675 were downregulated by H2 O2 in CPCs, but melatonin treatment could counter this alteration. Furthermore, knockdown of H19 or miR-675 blocked antisenescence actions of melatonin on H2 O2 -treated CPCs. It was further verified that H19-derived miR-675 targeted at the 3'UTR of USP10, which resulted in the downregulation of p53 and p21 proteins. In summary, melatonin antagonized premature senescence of CPCs via H19/miR-675/USP10 pathway, which provides new insights into pharmacological actions and potential applications of melatonin on the senescence of CPCs.
authors.affiliation: Department of Pharmacology (The State-Province Key Laboratories of Biomedicine-Pharmaceutics of China), Harbin Medical University, Harbin, China.
authors.forename: Benzhi
authors.initials: B
authors.lastname: Cai
authors.affiliation: Department of Pharmacology (The State-Province Key Laboratories of Biomedicine-Pharmaceutics of China), Harbin Medical University, Harbin, China.
authors.forename: Wenya
authors.initials: W
authors.lastname: Ma
authors.affiliation: Department of Pharmacology (The State-Province Key Laboratories of Biomedicine-Pharmaceutics of China), Harbin Medical University, Harbin, China.
authors.forename: Chongwei
authors.initials: C
authors.lastname: Bi
authors.affiliation: Department of Pharmacology (The State-Province Key Laboratories of Biomedicine-Pharmaceutics of China), Harbin Medical University, Harbin, China.
authors.forename: Fan
authors.initials: F
authors.lastname: Yang
authors.affiliation: Department of Pharmacology (The State-Province Key Laboratories of Biomedicine-Pharmaceutics of China), Harbin Medical University, Harbin, China.
authors.forename: Lai
authors.initials: L
authors.lastname: Zhang
authors.affiliation: Department of Pharmacology (The State-Province Key Laboratories of Biomedicine-Pharmaceutics of China), Harbin Medical University, Harbin, China.
authors.forename: Zhenbo
authors.initials: Z
authors.lastname: Han
authors.affiliation: Department of Pharmacology (The State-Province Key Laboratories of Biomedicine-Pharmaceutics of China), Harbin Medical University, Harbin, China.
authors.forename: Qi
authors.initials: Q
authors.lastname: Huang
authors.affiliation: Department of Pharmacology (The State-Province Key Laboratories of Biomedicine-Pharmaceutics of China), Harbin Medical University, Harbin, China.
authors.forename: Fengzhi
authors.initials: F
authors.lastname: Ding
authors.affiliation: Department of Pharmacology (The State-Province Key Laboratories of Biomedicine-Pharmaceutics of China), Harbin Medical University, Harbin, China.
authors.forename: Yuan
authors.initials: Y
authors.lastname: Li
authors.affiliation: Department of Pharmacology (The State-Province Key Laboratories of Biomedicine-Pharmaceutics of China), Harbin Medical University, Harbin, China.
authors.forename: Gege
authors.initials: G
authors.lastname: Yan
authors.affiliation: Department of Pharmacology (The State-Province Key Laboratories of Biomedicine-Pharmaceutics of China), Harbin Medical University, Harbin, China.
authors.forename: Zhenwei
authors.initials: Z
authors.lastname: Pan
authors.affiliation: Department of Pharmacology (The State-Province Key Laboratories of Biomedicine-Pharmaceutics of China), Harbin Medical University, Harbin, China.|Department of Pharmacology and Therapeutics, Melbourne School of Biomedical Sciences, Faculty of Medicine, Dentistry and Health Sciences, University of Melbourne, Melbourne, Vic., Australia.
authors.forename: Baofeng
authors.initials: B
authors.lastname: Yang
authors.affiliation: Department of Pharmacology (The State-Province Key Laboratories of Biomedicine-Pharmaceutics of China), Harbin Medical University, Harbin, China.|The Key Laboratory of Cardiovascular Research, Ministry of Education, Harbin Medical University, Harbin, China.
authors.forename: Yanjie
authors.initials: Y
authors.lastname: Lu
mesh_terms: D020413:3' Untranslated Regions; D000818:Animals; D016922:Cellular Senescence / Q000187:drug effects* / Q000235:genetics; D055785:Gene Knockdown Techniques; D006861:Hydrogen Peroxide / Q000494:pharmacology; D008550:Melatonin / Q000378:metabolism / Q000494:pharmacology*; D051379:Mice; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D032383:Myocytes, Cardiac / Q000166:cytology / Q000378:metabolism*; D019009:Proto-Oncogene Proteins c-kit / Q000235:genetics / Q000378:metabolism; D062085:RNA, Long Noncoding / Q000235:genetics / Q000378:metabolism*; D013234:Stem Cells / Q000166:cytology / Q000378:metabolism*; D043222:Ubiquitin Thiolesterase / Q000235:genetics / Q000378:metabolism
chemical_list: D020413:3' Untranslated Regions; C094335:H19 long non-coding RNA; C574758:MIRN675 microRNA, mouse; D035683:MicroRNAs; D062085:RNA, Long Noncoding; C579090:USP10 protein, mouse; D006861:Hydrogen Peroxide; D019009:Proto-Oncogene Proteins c-kit; D043222:Ubiquitin Thiolesterase; D008550:Melatonin
keywords: H19; cardiac progenitor cells; melatonin; miR-675; p53; senescence