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 renin-angiotensin system (RAS) genes polymorphism have been associated with blood pressure (BP) response to antihypertensives drugs and may also influence the variability in visit-to-visit BP. Here we have investigated the association of RAS gene polymorphism with response to three classes of antihypertensive drugs (atenolol, amlodipine and enalapril) and also with genetic factor which may influence the variability in visit-to-visit BP. Total of 230 participants of south Indian ethnicity and are under the medication of any of these three classes of drugs were enrolled. The four polymorphisms analyzed were AGT M235T (rs699), ACE I/D (rs4340) and G2350A (rs4343) and AT1R A1166C (rs5186) were genotyped in all patients and were analyzed for association. Significant association with visit-to-visit variance in BP was found in ACE G2350A variant with the diastolic blood pressure (DBP) and a high significance was observed in AT1R A1166C variant with both systolic blood pressure (SBP) (p < 0.001) and DBP (p < 0.001). Further, we did not observe any significant association between drug response and RAS gene polymorphisms. The present study revealed significant association of visit-to-visit BP variability with ACE G2350A and AT1R A1166C polymorphisms in essential hypertensive subjects. However results need to be replicate in larger population.Current Pharmacogenomics and Personalized Medicine (Formerly Current Pharmacogenomics) 05/2015; Volume 13,(2 Issues, 2015). DOI:10.2174/1875692113666150420225829
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ABSTRACT: Proteins of the striatin family (striatins 1-4; sizes ranging from 90 to 110 kDa on SDS-polyacrylamide gel electrophoresis) are highly homologous in their amino acid sequences but can differ in their cell-type-specific gene expression patterns and biological functions. In various cell types, we have found one, two or three polypeptides of this evolutionarily old and nearly ubiquitous family of proteins known to serve as scaffold proteins for diverse protein complexes. Light and electron microscopic immunolocalization methods have revealed striatins in mammalian cell-cell adherens junctions (AJs). In simple epithelia, we have localized striatins as constitutive components of the plaques of the subapical zonulae adhaerentes of cells, including intestinal, glandular, ductal and urothelial cells and hepatocytes. Striatins colocalize with E-cadherin or E-N-cadherin heterodimers and with the plaque proteins α- and β-catenin, p120 and p0071. In some epithelia and carcinomas and in cultured cells derived therefrom, striatins are also seen in lateral AJs. In stratified epithelia and in corresponding squamous cell carcinomas, striatins can be found in plaques of some forms of tessellate junctions. Moreover, striatins are major plaque proteins of composite junctions (CJs; areae compositae) in the intercalated disks connecting cardiomyocytes, colocalizing with other CJ molecules, including plectin and ankyrin-G. We discuss the “multimodulator” scaffold roles of striatins in the initiation and regulation of the formation of various complex particles and structures. We propose that striatins are included in the diagnostic candidate list of proteins that, in the CJs of human hearts, can occur in mutated forms in the pathogeneses of hereditary cardiomyopathies, as seen in some types of genetically determined heart damage in boxer dogs.Cell and Tissue Research 12/2014; 359(3):779-797. DOI:10.1007/s00441-014-2053-z · 3.33 Impact Factor
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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