title: Melatonin prevents neonatal dexamethasone induced programmed hypertension: histone deacetylase inhibition.
abstract: Adulthood hypertension can be programmed by corticosteroid exposure in early life. Oxidative stress, epigenetic regulation by histone deacetylases (HDACs), and alterations of renin-angiotensin system (RAS) are involved in the developmental programming of hypertension. We examined whether melatonin prevented neonatal dexamethasone (DEX)-induced programmed hypertension and how melatonin prevented these processes. We also examined whether HDAC inhibition by trichostatin A (TSA, a HDAC inhibitor) had similar effects. Male offspring were assigned to 5 groups (n=6/group): control, DEX, melatonin, DEX+melatonin, and DEX+TSA. Male rat pups were injected i.p. with DEX on day 1 (0.5mg/kg BW), day 2 (0.3mg/kg BW), and day 3 (0.1mg/kg BW) after birth. Melatonin was administered in drinking water at the dose of 0.01% during the lactation period. The DEX+TSA group received DEX and 0.5mg/kg TSA subcutaneous injection once daily for 1 week. All rats were killed at 16 weeks of age. Neonatal DEX exposure induced hypertension in male offspring at 16 weeks of age, which melatonin prevented. Neonatal DEX exposure decreased gene expression related to apoptosis, nephrogenesis, RAS, and sodium transporters. Yet DEX treatment increased protein levels of HDAC-1, -2, and -3 in the kidney. Melatonin therapy preserved the decreases of gene expression and decreased HDACs. Similarly, HDAC inhibition prevented DEX-induced programmed hypertension. In conclusion, melatonin therapy exerts a long-term protection against neonatal DEX-induced programmed hypertension. Its beneficial effects include alterations of RAS components and inhibition of class I HDACs. Given that the similar protective effects of melatonin and TSA, melatonin might inhibit HDACs to epigenetic regulation of hypertension-related genes to prevent programmed hypertension.
authors.affiliation: Department of Pediatrics, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University, College of Medicine, Kaohsiung, Taiwan. Electronic address: tainyl@hotmail.com.
authors.forename: Ting-Hsin
authors.initials: TH
authors.lastname: Wu
authors.affiliation: Department of Pediatrics, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University, College of Medicine, Kaohsiung, Taiwan.
authors.forename: Hsuan-Chang
authors.initials: HC
authors.lastname: Kuo
authors.affiliation: Department of Pediatrics, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University, College of Medicine, Kaohsiung, Taiwan.
authors.forename: I-Chun
authors.initials: IC
authors.lastname: Lin
authors.affiliation: Department of Pediatrics, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University, College of Medicine, Kaohsiung, Taiwan.
authors.forename: Shao-Ju
authors.initials: SJ
authors.lastname: Chien
authors.affiliation: Department of Pediatrics, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University, College of Medicine, Kaohsiung, Taiwan; Department of Traditional Chinese Medicine, Chang Gung University, Linkow, Taiwan.
authors.forename: Li-Tung
authors.initials: LT
authors.lastname: Huang
authors.affiliation: Department of Pediatrics, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University, College of Medicine, Kaohsiung, Taiwan; Center for Translational Research in Biomedical Sciences, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University, College of Medicine, Kaohsiung, Taiwan.
authors.forename: You-Lin
authors.initials: YL
authors.lastname: Tain
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D001794:Blood Pressure / Q000187:drug effects; D001835:Body Weight / Q000187:drug effects; D003907:Dexamethasone; D005786:Gene Expression Regulation / Q000187:drug effects; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D006655:Histone Deacetylases / Q000378:metabolism*; D006877:Hydroxamic Acids / Q000494:pharmacology; D006973:Hypertension / Q000139:chemically induced / Q000378:metabolism* / Q000503:physiopathology / Q000517:prevention & control; D007668:Kidney / Q000187:drug effects / Q000473:pathology; D008297:Male; D008550:Melatonin / Q000494:pharmacology* / Q000627:therapeutic use; D009929:Organ Size / Q000187:drug effects; D018384:Oxidative Stress / Q000187:drug effects; D017207:Rats, Sprague-Dawley; D012084:Renin-Angiotensin System / Q000187:drug effects / Q000235:genetics
chemical_list: D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; C012589:trichostatin A; D003907:Dexamethasone; D006655:Histone Deacetylases; D008550:Melatonin
keywords: Asymmetric dimethylarginine; Histone deacetylase; Hypertension; Melatonin; Oxidative stress; Renin–angiotensin system