title: Differential ERK1/2 Signaling and Hypertrophic Response to Endothelin-1 in Cardiomyocytes from SHR and Wistar-Kyoto Rats: A Potential Target for Combination Therapy of Hypertension.
abstract: Extracellular signal regulated kinase½ (ERK1/2) signaling is critical to endothelin-1 (ET-1)-induced cardiomyocyte hypertrophy. This study was to investigate ERK1/2 signaling and hypertrophic response to ET-1 stimulation in cardiomyocytes (CMs) from spontaneous hypertensive rats (SHR) and normotensive Wistar-Kyoto rats (WKY). Primary neonatal SHR and WKY CMs were exposed to ET-1 for up to 24 hrs. Minimal basal ERK1/2 phosphorylation was present in WKY CMs, while a significant baseline ERK1/2 phosphorylation was observed in SHR CMs. ET-1 induced a time- and dose-dependent increase in ERK1/2 phosphorylation in both SHR and WKY CMs. However, ET-1-induced ERK1/2 activation occurred much earlier with significantly higher peak phosphorylation level, and stayed elevated for longer duration in SHR CMs than that in WKY CMs. ET-1-induced hypertrophic response was more prominent in SHR CMs than that in WKY CMs as reflected by increased cell surface area, intracellular actin density, and protein synthesis. Pre-treatment with ERK1/2 phosphorylation inhibitor PD98059 completely prevented ET-1-induced ERK1/2 phosphorylation and increases in cell surface area and protein synthesis in SHR and WKY CMs. The specific PI3 kinase inhibitor LY294002 blocked ET-1-induced Akt and ERK1/2 phosphorylation, and protein synthesis in CMs. These data indicated that ERK1/2 signaling was differentially enhanced in CMs, and was associated with increased cardiac hypertrophic response to ET-1 in SHR. ET-1-induced ERK1/2 activation and cardiac hypertrophy appeared to be mediated via PI3 kinase/Akt signaling in SHR and WKY. The differential ERK1/2 activation in SHR CMs by ET-1 might represent a potential target for combination therapy of hypertension.
authors.forename: Li-An
authors.initials: LA
authors.lastname: Zhu
authors.affiliation: Department of Geriatrics, Renji Hospital, Shanghai Jiao Tong University School of Medicine, 145 Shan-Dong Middle Road, Shanghai 200001, China. fangny@sh163.net.
authors.forename: Ning-Yuan
authors.initials: NY
authors.lastname: Fang
authors.forename: Ping-Jin
authors.initials: PJ
authors.lastname: Gao
authors.forename: Xian
authors.initials: X
authors.lastname: Jin
authors.forename: Hai-Ya
authors.initials: HY
authors.lastname: Wang
authors.affiliation: Davis Heart & Lung Research Institute, the Ohio State University Medical Center, DHLRI Suite 200; 473 West 12th Ave, Columbus, OH 43210, USA. zhenguo.liu@osumc.edu.
authors.forename: Zhenguo
authors.initials: Z
authors.lastname: Liu
mesh_terms: D000818:Animals; D015153:Blotting, Western; D006332:Cardiomegaly / Q000378:metabolism* / Q000473:pathology; D018929:Cell Culture Techniques; D048429:Cell Size / Q000187:drug effects; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D004359:Drug Therapy, Combination; D019332:Endothelin-1 / Q000378:metabolism / Q000494:pharmacology*; D006973:Hypertension / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D007150:Immunohistochemistry; D020935:MAP Kinase Signaling System / Q000187:drug effects*; D032383:Myocytes, Cardiac / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010766:Phosphorylation; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors; D011918:Rats, Inbred SHR; D011921:Rats, Inbred WKY
chemical_list: D019332:Endothelin-1; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt