Striatin-dependent membrane estrogen receptor signaling and vasoprotection by estrogens.
ABSTRACT It is well known that cardiovascular disease is less frequent in premenopausal women compared with men but rises rapidly in postmenopausal women. Such early observations led to the hypothesis that estrogen therapy will reduce the risk of postmenopausal women developing cardiovascular disease.(1) However, observational studies have led to conflicting results with some studies reporting reductions in cardiovascular disease in postmenopausal women taking estrogens whilst others observed no beneficial effects.(2) Rather increases in the risk of coronary heart disease and stroke have been reported, particularly for women who are older and those with a long hormone-free interval.(3) Such findings have led to the speculation that estrogens have competing cardiovascular effects-beneficial and detrimental and this has intensified efforts to better understand the range of cardiovascular effects mediated by estrogens and their signaling mechanisms, the ultimate aim being to develop new therapies for women that exert the beneficial effects of estrogen whilst minimizing potentially harmful effects. To achieve this aim, new studies to better understand both nuclear and membrane estrogen receptor (ER)-mediated signaling in target tissues such as the heart and blood vessels, immune cells and other target tissues are in progress. In this issue of Circulation, Moens and colleagues provide novel insights on the importance of membrane ER-mediated signaling pathways in blood vessels for vasoprotection and vascular gene regulation.(4).
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ABSTRACT: The primary adrenal cortical steroid hormones, aldosterone, and the glucocorticoids cortisol and corticosterone, act through the structurally similar mineralocorticoid (MR) and glucocorticoid receptors (GRs). Aldosterone is crucial for fluid, electrolyte, and hemodynamic homeostasis and tissue repair; the significantly more abundant glucocorticoids are indispensable for energy homeostasis, appropriate responses to stress, and limiting inflammation. Steroid receptors initiate gene transcription for proteins that effect their actions as well as rapid non-genomic effects through classical cell signaling pathways. GR and MR are expressed in many tissues types, often in the same cells, where they interact at molecular and functional levels, at times in synergy, others in opposition. Thus the appropriate balance of MR and GR activation is crucial for homeostasis. MR has the same binding affinity for aldosterone, cortisol, and corticosterone. Glucocorticoids activate MR in most tissues at basal levels and GR at stress levels. Inactivation of cortisol and corticosterone by 11β-HSD2 allows aldosterone to activate MR within aldosterone target cells and limits activation of the GR. Under most conditions, 11β-HSD1 acts as a reductase and activates cortisol/corticosterone, amplifying circulating levels. 11β-HSD1 and MR antagonists mitigate inappropriate activation of MR under conditions of oxidative stress that contributes to the pathophysiology of the cardiometabolic syndrome; however, MR antagonists decrease normal MR/GR functional interactions, a particular concern for neurons mediating cognition, memory, and affect. © 2014 American Physiological Society. Compr Physiol 4:965-994, 2014.07/2014; 4(3):965-94. DOI:10.1002/cphy.c130044
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ABSTRACT: Renin-angiotensin system (RAS) polymorphisms have been studied as candidate risk factors for hypertension with inconsistent results, possibly due to heterogeneity among various genetic and environmental factors. A case-control association study was conducted to investigate a possible involvement of polymorphisms of three RAS genes:AGT M235T (rs699),ACEI/D (rs4340) and G2350A (rs4343), andAGTR1A1166C (rs5186) in essential hypertensive patients. A total of 211 cases and 211 controls were recruited for this study. Genotyping was performed using PCR-RFLP method. The genotype and allele distribution of the M235T variant differed significantly in hypertensives and normotensives (OR-CI = 2.62 (1.24–5.76), 𝑃 = 0.006; OR-CI = 0.699 (0.518–0.943),𝑃 = 0.018), respectively. When the samples were segregated based on sex, the 235TT genotype and T allele were predominant in the female patients (OR-CI = 5.68 (1.60-25.10), 𝑃 = 0.002; OR-CI = 0.522 (0.330–0.826), 𝑃 = 0.005) as compare to the male patients (OR-CI = 1.54 (1.24–5.76), 𝑃 = 0.34; OR-CI = 0.874 (0.330–0.826), 𝑃 = 0.506), respectively. For ACE DD variant, we found overrepresentation of “I”-allele (homozygous II and heterozygous ID) in unaffected males which suggest its protective role in studied population (OR-CI = 0.401 (0.224–0.718); 𝑃 = 0.0009). The M235T variant of the AGT is significantly associated with female hypertensives andACE DD variant could be a risk allele for essential hypertension in south India.01/2014; DOI:10.1155/2014/538053.