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Estrogen attenuates coupling factor 6-induced salt-sensitive hypertension and cardiac systolic dysfunction in mice.

Abstract
In male coupling factor 6 (CF6)-overexpressing transgenic (TG) mice, a high-salt diet induces hypertension and cardiac systolic dysfunction with excessive reactive oxygen species generation. However, the role of gender in CF6-mediated pathophysiology is unknown. We investigated the effects of ovariectomy and estrogen replacement on hypertension, cardiac dysfunction and Rac1 activity, which activates radical generation and the mineralocorticoid receptor, in female TG mice. Fifteen-week-old male and female TG and wild-type (WT) mice were fed a normal- or high-salt diet for 60 weeks. Systolic and diastolic blood pressures were higher in the TG mice fed a high-salt diet than in those fed a normal-salt diet at 20-60 weeks in males but only at 60 weeks in females. The blood pressure elevation under high-salt diet conditions was concomitant with a decrease in left ventricular fractional shortening. In the WT mice, neither blood pressure nor cardiac systolic function was influenced by a high-salt diet. In the female TG mice, bilateral ovariectomy induced hypertension with cardiac systolic dysfunction 8 weeks after the initiation of a high-salt diet. The ratios of Rac1 bound to guanosine triphosphate (Rac1-GTP) to total Rac1 in the heart and kidneys were increased in the ovariectomized TG mice, and estrogen replacement abolished the CF6-mediated pathophysiology induced under the high-salt diet conditions. The overexpression of CF6 induced salt-sensitive hypertension, complicated by systolic cardiac dysfunction, but its onset was delayed in females. Estrogen has an important role in the regulation of CF6-mediated pathophysiology, presumably via the downregulation of Rac1.
AuthorsKei Izumiyama, Tomohiro Osanai, Shigeki Sagara, Yuko Yamamoto, Taihei Itoh, Takanori Sukekawa, Fumie Nishizaki, Koji Magota, Ken Okumura
JournalHypertension research : official journal of the Japanese Society of Hypertension (Hypertens Res) Vol. 35 Issue 5 Pg. 539-46 (May 2012) ISSN: 1348-4214 [Electronic] England
PMID22258022 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References
  • Estrogens
  • Neuropeptides
  • Oxidative Phosphorylation Coupling Factors
  • Rac1 protein, mouse
  • Sodium Chloride, Dietary
  • Guanosine Triphosphate
  • F(6) ATPase
  • Mitochondrial Proton-Translocating ATPases
  • rac GTP-Binding Proteins
  • rac1 GTP-Binding Protein
Topics
  • Animals
  • Estrogens (pharmacology)
  • Female
  • Guanosine Triphosphate (metabolism)
  • Hypertension (chemically induced, physiopathology)
  • Kidney (metabolism)
  • Male
  • Mice
  • Mice, Transgenic
  • Mitochondrial Proton-Translocating ATPases (physiology)
  • Myocardium (metabolism)
  • Neuropeptides (metabolism)
  • Ovariectomy
  • Oxidative Phosphorylation Coupling Factors (physiology)
  • Sex Factors
  • Sodium Chloride, Dietary (adverse effects, pharmacology)
  • Ventricular Dysfunction, Left (drug therapy, physiopathology)
  • rac GTP-Binding Proteins (metabolism)
  • rac1 GTP-Binding Protein

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