17beta-estradiol reduces cardiac hypertrophy mediated through the up-regulation of PI3K/Akt and the suppression of calcineurin/NF-AT3 signaling pathways in rats.
This study was designed to determine the effects of 17beta-estradiol (E2) in overcoming the cardiac over-loading and cardiac fibrosis in rats. E2 (100 ng/kg) or oil was applied in female Sprague-Dawley rats with or without bilateral ovariectomy and with or without coarctation of the abdominal aorta after 4 or 8 days. By post-operative day 4, the heart weight, the left ventricular weight, the latent form of MMP-2 in rat hearts with or without the ovary intact had significantly increased while these changes were reversed after E2 treatment. Although animals with the ovaries intact overcame the hypertrophic effects and the consumption of MMP-2, these effects were not restored in ovariectomized animals in which more fibrosis could be found by day 8. Among the IGF-I signaling, the levels of IGF-I, the activities of PI3K-Akt for cardiomyocyte survival, and MEK-ERKs for non-cardiomyocyte proliferation pathways had significantly increased by day 4. These increasing trends were enhanced by E2 treatment. However, down-regulation was only observed on day 8 in ovariectomized animals. Similarly, elevated expressions of the steady-state mRNA of IGF-I, IGF-IR, and Cox vb were observed on day 4 in animals with the ovaries intact and these expressions were enhanced by E2 treatment. In contrast, down-regulation on day 8 in ovariectomized animals was not enhanced by E2. The calcineurin/NFAT-3 pathway was suppressed on day 4 but was elevated on day 8 in ovariectomized animals. These findings indicate that signaling pathways may be plausible mechanisms for the cardiac protective effects of E2 administration.
Wu
Chieh-Hsi
CH
Department of Biological Science and Technology, China Medical University, Taichung, Taiwan, R.O.C.
Liu
Jer-Yuh
JY
Wu
Jia-Ping
JP
Hsieh
Yi-Hsien
YH
Liu
Chung-Jung
CJ
Hwang
Jin-Ming
JM
Lee
Shin-Da
SD
Chen
Li-Mien
LM
Chang
Mu-Hsin
MH
Kuo
Wei-Wen
WW
Shyu
Jyh-Cherng
JC
Tsai
Jen-Hsiang
JH
Huang
Chih-Yang
CY
D000818:Animals; D001017:Aortic Coarctation; D019703:Calcineurin / Q000378:metabolism*; D002470:Cell Survival / Q000187:drug effects; D004195:Disease Models, Animal; D004958:Estradiol / Q000627:therapeutic use*; D005260:Female; D005355:Fibrosis / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D006321:Heart / Q000187:drug effects; D006352:Heart Ventricles / Q000187:drug effects / Q000473:pathology; D017379:Hypertrophy, Left Ventricular / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D050778:NFATC Transcription Factors / Q000378:metabolism*; D009929:Organ Size / Q000187:drug effects; D010052:Ovariectomy; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction; D015854:Up-Regulation
D050778:NFATC Transcription Factors; D004958:Estradiol; D019869:Phosphatidylinositol 3-Kinases; C494920:Akt1 protein, rat; D051057:Proto-Oncogene Proteins c-akt; D019703:Calcineurin; D020778:Matrix Metalloproteinase 2