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Women have a lower incidence of cardiovascular diseases (CVD) than men at a similar age but the reverse is the case after menopause, indicating a possible protective effect of estrogen on cardiometabolic function. Although various hormonal therapies have been formulated to combat the CVD risks in postmenopausal state, the beneficial effects have not been consistent. Obesity with insulin resistance (IR) is closely linked to CVD risks while ovariectomized rodents have been shown to mimic a state of obesity and IR. We therefore hypothesized that low-dose spironolactone would ameliorate obesity and IR in estrogendeprived rats by replenishing estrogen and suppressing elevated glycogen synthase kinase-3 (GSK-3). Ten-week-old female Wistar rats were divided into 4 groups: sham-operated (SHM), spironolactone (SPL; 0.25 mg/kg), and ovariectomized (OVX) rats treated with or without spironolactone daily for 8 weeks. Results showed that estrogen deprivation through ovariectomy caused increased body mass gain and visceral adiposity that are accompanied by increased HOMA-IR, HOMA-[beta], 1-hour postload glucose, glucose intolerance, platelet/lymphocyte ratio, plasma insulin, atherogenic dyslipidemia, uric acid, GSK-3, corticosterone, and aldosterone and depressed 17[beta]-estradiol. However, treatment of OVX rats with spironolactone ameliorated all these effects. Taken together, the results demonstrate that treatment with low-dose spironolactone improves obesity and IR, which appears to involve replenishment of estrogen and suppression of GSK-3 along with circulating mineralocorticoid and glucocorticoid. The findings imply a positive cardiometabolic effect of low-dose spironolactone usage in estrogen-deprived conditions.Key words: aldosterone, cardiometabolic syndrome, estrogen replacement therapy, GSK-3, mineralocorticoid receptor, spironolactone.Les maladies cardiovasculaires (MCV) sont moins frequentes chez les femmes que chez les hommes d'ages similaires, mais la situation s'inverse apres la menopause, ce qui pointe vers un effet protecteur des aestrogenes sur la fonction cardiometabolique. Bien que diverses presentations de therapies hormonales aient ete proposees en vue de combattre le risque de MCV apres la menopause, les bienfaits obtenus ont ete inegaux. L'obesite avec resistance a l'insuline (RI) est intimement liee aux risques de MCV, et il est decrit que les rongeurs ovariectomises miment un etat d'obesite avec RI. Nous avons donc pose l'hypothese selon laquelle une faible dose de spironolactone permet d'ameliorer l'etat d'obesite avec RI chez des rates carencees en aestrogenes en retablissant les taux d'aestrogenes et en inhibant la hausse de la GSK-3 (pour glycogen synthase kinase-3). Nous avons reparti des rates Wistar de 10 semaines dans 4 groups : intervention factice (<< sham >>), ovariectomie (OVX), ainsi que deux groupes semblables avec en plus l'administration de spironolactone a raison de 0,25 mg/kg quotidiennement pendant 8 semaines. Les resultats ont montre que la carence en aestrogenes provoquee par l'OVX entrainait une augmentation de la prise de poids et une accumulation de tissu adipeux visceral accompagnees d'une augmentation des taux d'HOMA-IR, d'HOMA-[beta], de la glycemie 1 heure apres l'administration d'une charge glycemique, du ratio plaquettes/lymphocytes, des taux plasmatiques d'insuline, d'acide urique, de GSK 3, de corticosterone et d'aldosterone avec un abaissement des taux d'estradiol 17[beta], ainsi qu' intolerance au glucose et une dyslipidemie atherogene. Mais l'administration de spironolactone a permis d'attenuer ces effets chez les rates OVX. Dans l'ensemble, les resultats montrent que l'administration de faibles doses de spironolactone permet d'attenuer l'obesite et la RI, ce qui semble lie au retablissement des taux d'aestrogenes, avec l'inhibition de la GSK-3, ainsi que des taux de mineralocorticoides et de glucocorticoides en circulation. Les resultats pointent vers un effet cardiometabolique avantageux du spironolactone a faible dose utilise en situation de carence en aestrogenes. [Traduit par la Redaction]Mots-cles : aldosterone, syndrome cardiometabolique, therapie de substitution des aestrogenes, GSK-3, recepteur des mineralocorticoides, spironolactone., IntroductionCardiovascular disease (CVD) has been the major cause of death for several decades and is expected to remain so until 2030 (Mathers and Loncar 2006). It has been shown that [...]

Estrogen deficiency has been associated with increased incidence of cardiovascular diseases, and recent clinical trials of standard formulations of hormonal therapies have not demonstrated consistent beneficial effects. Estrogen-progestin therapy has been used as exogenous estrogen to normalize depressed estrogen level during menopause. Ovariectomized rodents mimic an estrogen-deficient state in that they develop cardiometabolic dysfunction, including insulin resistance (IR). We therefore hypothesized that hormonal therapy with combined oral contraceptive steroids, ethinylestradiol-levonorgestrel (EEL), improves IR, obesity, and glycogen synthase kinase-3 (GSK-3) through reduction of circulating mineralocorticoid in ovariectomized rats. Twelve-week-old female Wistar rats were divided into 4 groups: sham-operated (SHM) and ovariectomized (OVX) rats were treated with or without EEL (1.0 [micro]g ethinylestradiol and 5.0 [micro]g levonorgestrel) daily for 8 weeks. Results showed that OVX or SHM + EEL treated rats had increased HOMA-IR (homeostatic model assessment of IR), 1 h postload glucose, HOMA-[beta], triglycerides (TG), total cholesterol (TC), TC/HDL cholesterol, TG/HDL cholesterol, plasma insulin, GSK-3, corticosterone, and aldosterone. On the other hand, OVX + EEL treatment ameliorated all these effects except that of aldosterone. Taken together, the results demonstrate that oral hormonal replacement with EEL improves IR and pancreatic [beta]-cell function and suppresses GSK-3 and glucocorticoid independent of circulating aldosterone, suggesting a positive cardiometabolic effect of oral EEL therapy in estrogen-deficient rats. Key words: cardiometabolic syndrome, oral contraceptive, hormone replacement therapy, GSK-3, aldosterone. On a associe le deficit en restrogenes a une augmentation de l'incidence des maladies cardiovasculaires, et de recents essais cliniques portant sur des presentations standard d'hormonotherapies n'ont pas montre d'effets avantageux consequents. Le traitement par l'association d'restrogenes avec des progestatifs a ete utilise en tant qu'restrogenes exogenes en vue de ramener les taux d'restrogenes deprimes a la normale pendant la menopause. L'ovariectomie chez le rongeur est un modele de deficit restrogenique par la formation d'un dysfonctionnement cardiometabolique, y compris une resistance a l'insuline (RI). Par consequent, nous avons formule une hypothese selon laquelle la combinaison d'une hormonotherapie avec des steroides contraceptifs oraux--ethinylestradiol-levonorgestrel (EEL)--permet d'attenuer la RI, l'obesite et l'effet de la GSK-3 (glycogen synthase kinase-3) par la diminution des taux de mineralocorticoides en circulation chez des rates ovariectomisees. Nous avons reparti des rates Wistar de 12 semaines dans 4 groupes: intervention chirurgicale factice (SHM) ou ovariectomie (OVX) avec ou sans administration quotidienne d'EEL (1,0 [micro]g d'ethinylestradiol et 5,0 [micro]g de levonorgestrel) pendant 8 semaines. Les resultats ont montre que les rates des groupes OVX et SHM + EEL presentaient une hausse de l'HOMA-IR (pour << homeostatic model assessment of insulin resistance >>), de la glycemie 1 h apres l'administration de glucose et de l'HOMA-[beta], ainsi que des taux de triglycerides (TG) et de cholesterol total (CT), des rapports CT/cholesterol HDL et TG/cholesterol HDL, avec une augmentation des taux plasmatiques d'insuline, de GSK-3, de corticosterone et d'aldosterone. Inversement, tous ces effets s'amelioraient dans le groupe OVX + EEL, sauf pour l'aldosterone. Dans l'ensemble, ces resultats montrent que la substitution hormonale avec de l'EEL par voie orale permet d'attenuer la RI et d'ameliorer le fonctionnement des cellules pancreatiques [beta], avec une diminution des taux de GSK-3 et de glucocorticoides independante de l'aldosterone. Cela laisse entrevoir un effet cardiometabolique positif pour le traitement par l'EEL par voie orale chez les rates en deficit restrogenique. [Traduit par la Redaction] Mots-cles: syndrome cardiometabolique, contraceptif oral, traitement par substitution hormonale, GSK-3, aldosterone., Introduction Sexual dimorphisms in the development of cardiovascular diseases (CVDs) are well documented in both human and animal studies. The incidence of CVDs among women increases sharply after menopause (Mendelsohn [...]

Interstitial lung diseases can result in poor patient outcomes, especially in idiopathic pulmonary fibrosis (IPF), a severe interstitial lung disease with unknown causes. The lack of treatment options requires further understanding of the pathological process/mediators. Membrane-associated RING-CH 8 (MARCH8) has been implicated in immune function regulation and inflammation, however, its role in the development of pulmonary fibrosis and particularly the fibroblast to myofibroblast transition (FMT) remains a gap in existing knowledge. In this study, we demonstrated decreased MARCH8 expression in patients with IPF compared with non-PF controls and in bleomycin-induced PF. TGF-β dose- and time-dependently decreased MARCH8 expression in normal and IPF human lung fibroblast (HLFs), along with induction of FMT markers α-SMA, collagen type I (Col-1), and fibronectin (FN). Interestingly, overexpression of MARCH8 significantly suppressed TGF-β-induced expression of a-SMA, Col-1, and FN. By contrast, the knockdown of MARCH8 using siRNA upregulated basal expression of α-SMA/Col-1/FN. Moreover, MARCH8 knockdown enhanced TGF-β-induced FMT marker expression. These data clearly show that MARCH8 is a critical "brake" for FMT and potentially affects PF. We further found that TGF-β suppressed MARCH8 mRNA expression and the proteasome inhibitor MG132 failed to block MARCH8 decrease induced by TGF-β. Conversely, TGF-β decreases mRNA levels of MARCH8 in a dose- and time-dependent manner, suggesting the transcriptional regulation of MARCH8 by TGF-β. Mechanistically, MARCH8 overexpression suppressed TGF-β-induced Smad2/3 phosphorylation, which may account for the observed effects. Taken together, this study demonstrated an unrecognized role of MARCH8 in negatively regulating FMT and profibrogenic responses relevant to interstitial lung diseases. [ABSTRACT FROM AUTHOR]

Context: Studies have shown that cardiac triglyceride accumulation and impaired Na+-K+-ATPase activity are linked to diabetes- related cardiovascular disease, particularly in women. Objectives: We hypothesised that allopurinol (ALL) and valproic acid (VPA) treatment would improve cardiac triglyceride and Na+-K+-ATPase activity independent of circulating aldosterone in Combined Oral Contraceptive (COC)-induced dysglycemia Materials and methods: Rats received COC (1.0 μg ethinylestradiol and 5.0 μg levonorgestrel; po) with or without ALL (1 mg; po) and VPA (20 mg; po) for 6 weeks. Results: COC-treatment led to impaired glucose tolerance, accumulated abdominal fat, dyslipidemia, elevated plasma MDA, PAI-1 and aldosterone levels and also reduced plasma nitric oxide bioavailability and cardiac Na+-K+-ATPase activity. However, either ALL or VPA treatment ameliorated these alterations comparably independent of elevated aldosterone level Discussion and conclusion: Our results suggest that either ALL or VPA would improve cardiac TG and Na+-K+-ATPase activity comparably in COC-treated rats, regardless of circulating aldosterone level. [ABSTRACT FROM AUTHOR]

Idiopathic pulmonary fibrosis (IPF) is the most common chronic interstitial lung disease and is characterized by progressive scarring of the lung. Transforming growth factor-β (TGF-β) signaling plays an essential role in IPF and drives fibroblast to myofibroblast transition (FMT). Dedicator of cytokinesis 2 (DOCK2) is known to regulate diverse immune functions by activating Rac and has been recently implicated in pleural fibrosis. We now report a novel role of DOCK2 in pulmonary fibrosis development by mediating FMT. In primary normal and IPF human lung fibroblasts (HLFs), TGF-β induced DOCK2 expression concurrent with FMT markers, smooth muscle α-actin (α-SMA), collagen-1, and fibronectin. Knockdown of DOCK2 significantly attenuated TGF-β-induced expression of these FMT markers. In addition, we found that the upregulation of DOCK2 by TGF-β is dependent on both Smad3 and ERK pathways as their respective inhibitors blocked TGF-β-mediated induction. TGF-β also stabilized DOCK2 protein, which contributes to increased DOCK2 expression. In addition, DOCK2 was also dramatically induced in the lungs of patients with IPF and in bleomycin, and TGF-β induced pulmonary fibrosis in C57BL/6 mice. Furthermore, increased lung DOCK2 expression colocalized with the FMT marker α-SMA in the bleomycin-induced pulmonary fibrosis model, implicating DOCK2 in the regulation of lung fibroblast phenotypic changes. Importantly, DOCK2 deficiency also attenuated bleomycin-induced pulmonary fibrosis and α-SMA expression. Taken together, our study demonstrates a novel role of DOCK2 in pulmonary fibrosis by modulating FMT and suggests that targeting DOCK2 may present a potential therapeutic strategy for the prevention or treatment of IPF. [ABSTRACT FROM AUTHOR]

Mesothelial to mesenchymal transition (MesoMT) is one of the crucial mechanisms underlying pleural fibrosis, which results in restrictive lung disease. DOCK2 (dedicator of cytokinesis 2) plays important roles in immune functions; however, its role in pleural fibrosis, particularly MesoMT, remains unknown. We found that amounts of DOCK2 and the MesoMT marker α-SMA (α-smooth muscle actin) were significantly elevated and colocalized in the thickened pleura of patients with nonspecific pleuritis, suggesting the involvement of DOCK2 in the pathogenesis of MesoMT and pleural fibrosis. Likewise, data from three different pleural fibrosis models (TGF-β [transforming growth factor-β], carbon black/bleomycin, and streptococcal empyema) consistently demonstrated DOCK2 upregulation and its colocalization with α-SMA in the pleura. In addition, induced DOCK2 colocalized with the mesothelial marker calretinin, implicating DOCK2 in the regulation of MesoMT. Our in vivo data also showed that DOCK2-knockout mice were protected from Streptococcus pneumoniae-induced pleural fibrosis, impaired lung compliance, and collagen deposition. To determine the involvement of DOCK2 in MesoMT, we treated primary human pleural mesothelial cells with the potent MesoMT inducer TGF-β. TGF-β significantly induced DOCK2 expression in a time-dependent manner, together with α-SMA, collagen 1, and fibronectin. Furthermore, DOCK2 knockdown significantly attenuated TGF-β-induced α-SMA, collagen 1, and fibronectin expression, suggesting the importance of DOCK2 in TGF-β-induced MesoMT. DOCK2 knockdown also inhibited TGF-β-induced Snail upregulation, which may account for its role in regulating MesoMT. Taken together, the current study provides evidence that DOCK2 contributes to the pathogenesis of pleural fibrosis by mediating MesoMT and deposition of neomatrix and may represent a novel target for its prevention or treatment. [ABSTRACT FROM AUTHOR]