Estradiol attenuates hypoxia-induced pulmonary endothelin-1 gene expression

Abstract

Earley, Scott, and Thomas C. Resta. Estradiol attenuates hypoxia-induced pulmonary endothelin-1 gene expression. Am J Physiol Lung Cell Mol Physiol 283: L86-L93, 2002. First published February 8, 2002 10.1152/ajplung.00476.2001.-The ovarian hormone 17␤-estradiol (E 2␤) attenuates chronic hypoxia-induced pulmonary hypertension. We hypothesized that E 2␤ attenuates this response to hypoxia by decreasing pulmonary expression of the vasoactive and mitogenic peptide endothelin-1 (ET-1). To test this hypothesis, we measured preproET-1 mRNA and ET-1 peptide levels in the lungs of adult female normoxic and hypoxic (24 h or 4 wk at barometric pressure ϭ 380 mmHg) rats with intact ovaries and in hypoxic ovariectomized (OVX) rats administered E 2␤ or vehicle via subcutaneous osmotic pumps. Hypoxic exposure increased lung preproET-1 mRNA levels in OVX vehicle-treated rats, but not in rats with intact ovaries. In addition, E 2␤ replacement prevented hypoxia-mediated increases in preproET-1 mRNA and ET-1 peptide expression. Considering that hypoxic induction of ET-1 gene expression is mediated by a hypoxia-inducible transcription factor(s) (HIF), we further hypothesized that E 2␤-induced attenuation of pulmonary ET-1 expression during hypoxia results from decreased HIF activity. We found that E 2␤ abolished HIFdependent increases in reporter gene activity. Further experiments demonstrated that overexpression of the transcriptional coactivator cAMP response element binding protein (CREB) binding protein (CBP)/p300, a factor common to both the estrogen receptor and HIF pathways, eliminated E 2␤-mediated attenuation of hypoxia-induced ET-1 promoter activity. We conclude that E 2␤ inhibits hypoxic induction of ET-1 gene expression by interfering with HIF activity, possibly through competition for limiting quantities of CBP/p300. pulmonary hypertension; hypoxia-inducible factor; reporter gene activity CHRONIC HYPOXIA (CH) is a consequence of prolonged residence at high altitude and pathological conditions that impair oxygenation of the blood, such as chronic obstructive pulmonary disease (COPD). Physiological responses to CH include hypoxic pulmonary vasoconstriction (HPV), pulmonary arterial remodeling, and polycythemia. Increased pulmonary vascular resistance and the resultant pulmonary hypertension associated with these responses lead to right ventricular hypertrophy and right heart failure. Epidemiological studies suggest that women with COPD exhibit a decreased risk of mortality compared with men (30), indicating that gender-specific factors may influence the development of hypoxia-induced pulmonary hypertension. In agreement with these observations, a previous study from our laboratory (26) has demonstrated that CH ovariectomized (OVX) rats develop more severe right ventricular hypertrophy and pulmonary arterial remodeling than either CH rats with intact ovaries or CH OVX rats administered the ovarian hormone 17␤-estradiol (E 2 ␤) during CH. However, the mechanisms by which E 2 ␤ exerts such protective influences in the hyp...

Relationship between Digit Ratio and Idiopathic Pulmonary Arterial Hypertension in Japanese Women

“…In addition, there seems to be a clear relationship between sex hormones and the vasoactive mediator endothelin, which is also important in the pathology of PAH. One study showed that estrogen attenuates hypoxia-induced pulmonary ET-1 gene expression in the lung tissue of adult female rats [12], while another found plasma basal levels of ET-1 increased in human males with low testosterone levels [7].…”

The Effects of Endogenous Sex Hormones and Acute Hypoxia on Vasoconstriction in Isolated Rat Pulmonary Artery Rings

“…Additionally, estrogen has been shown to downregulate endothelin-1, a potent vasoactive and mitogenic mediator [10]. Estrogen also regulates phosphorylation of proteins in the MAPK and ERK signaling pathways [14].…”

“…Several studies have investigated the role of sex hormones with regards to vasoreactivity of the pulmonary vasculature [7,10]. Both testosterone and estrogen have been shown to acutely affect vasoreactivity in various vascular beds [11,12].…”

“…These include increased production of nitric oxide and decreased expression of endothelin-1 as well as MAPK and ERK effects [10,[14][15][16][17]. Additionally, estrogen has been shown to have anti-inflammatory properties [2,18].…”

Novel Mechanisms Responsible for Postmenopausal Hypertension

“…Estradiol inhibits endothelin synthesis. 45,46 Thus, after menopause, this inhibitory effect would be lost. Endothelin synthesis can be upregulated by Ang II, 47 and ET A receptors have been shown to mediate Ang II hypertension in animal studies.…”