Cardiovascular diseases are a leading cause of mortality and disability worldwide. Hypertension, a major risk factor for these diseases, remains difficult to treat despite numerous drugs being ...available. In this issue of the JCI, Failer et al. show that the endogenous antiinflammatory agent developmental endothelial locus-1 (DEL-1) decreased blood pressure and cardiac and aortic hypertrophy in mouse models of hypertension through reduction in αvβ3 integrin-dependent metalloproteinase activity and immune cell recruitment, leading to reduced production of proinflammatory cytokines in cardiovascular tissues. This study offers an alternative in the treatment of hypertension-mediated organ damage through the immunomodulatory effect of DEL-1.
Estrogen receptor alpha (ERα) has been recognized now for several decades as playing a key role in reproduction and exerting functions in numerous nonreproductive tissues. In this review, we attempt ...to summarize the in vitro studies that are the basis of our current understanding of the mechanisms of action of ERα as a nuclear receptor and the key roles played by its two activation functions (AFs) in its transcriptional activities. We then depict the consequences of the selective inactivation of these AFs in mouse models, focusing on the prominent roles played by ERα in the reproductive tract and in the vascular system. Evidence has accumulated over the two last decades that ERα is also associated with the plasma membrane and activates non-nuclear signaling from this site. These rapid/nongenomic/membrane-initiated steroid signals (MISS) have been characterized in a variety of cell lines, and in particular in endothelial cells. The development of selective pharmacological tools that specifically activate MISS and the generation of mice expressing an ERα protein impeded for membrane localization have begun to unravel the physiological role of MISS in vivo. Finally, we discuss novel perspectives for the design of tissue-selective ER modulators based on the integration of the physiological and pathophysiological roles of MISS actions of estrogens.
In vertebrates, the octopeptide angiotensin II (AngII) is an important in vivo regulator of the cardiovascular system. It acts mainly through two G protein-coupled receptors, AT1 and AT2. To better ...understand distinctive features of these receptors, we carried out a phylogenetic analysis that revealed a mirror evolution of AT1 and AT2, each one split into two clades, separating fish from terrestrial receptors. It also revealed that hallmark mutations occurred at, or near, the sodium binding site in both AT1 and AT2. Electrostatics computations and molecular dynamics simulations support maintained sodium binding to human AT1 with slow ingress from the extracellular side and an electrostatic component of the binding free energy around -3kT, to be compared to around -2kT for human AT2 and the δ opioid receptor. Comparison of the sodium binding modes in wild type and mutated AT1 and AT2 from humans and eels indicates that the allosteric control by sodium in both AT1 and AT2 evolved during the transition from fish to amniota. The unusual S7.46N mutation in AT1 is mirrored by a L3.36M mutation in AT2. In the presence of sodium, the N7.46 pattern in amniota AT1 stabilizes the inward orientation of N3.35 in the apo receptor, which should contribute to efficient N3.35 driven biased signaling. The M3.36 pattern in amniota AT2 favours the outward orientation of N3.35 and the receptor promiscuity. Both mutations have physiological consequences for the regulation of the renin-angiotensin system.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Estrogen receptor alpha (ERα) activation functions AF-1 and AF-2 classically mediate gene transcription in response to estradiol (E2). A fraction of ERα is targeted to plasma membrane and elicits ...membrane-initiated steroid signaling (MISS), but the physiological roles of MISS in vivo are poorly understood. We therefore generated a mouse with a point mutation of the palmitoylation site of ERα (C451A-ERα) to obtain membrane-specific loss of function of ERα. The abrogation of membrane localization of ERα in vivo was confirmed in primary hepatocytes, and it resulted in female infertility with abnormal ovaries lacking corpora lutea and increase in luteinizing hormone levels. In contrast, E2 action in the uterus was preserved in C451A-ERα mice and endometrial epithelial proliferation was similar to wild type. However, E2 vascular actions such as rapid dilatation, acceleration of endothelial repair, and endothelial NO synthase phosphorylation were abrogated in C451A-ERα mice. A complementary mutant mouse lacking the transactivation function AF-2 of ERα (ERα-AF2 ⁰) provided selective loss of function of nuclear ERα actions. In ERα-AF2 ⁰, the acceleration of endothelial repair in response to estrogen–dendrimer conjugate, which is a membrane-selective ER ligand, was unaltered, demonstrating integrity of MISS actions. In genome-wide analysis of uterine gene expression, the vast majority of E2-dependent gene regulation was abrogated in ERα-AF2 ⁰, whereas in C451A-ERα it was nearly fully preserved, indicating that membrane-to-nuclear receptor cross-talk in vivo is modest in the uterus. Thus, this work genetically segregated membrane versus nuclear actions of a steroid hormone receptor and demonstrated their in vivo tissue-specific roles.
OBJECTIVE—Cardiac damage and vascular dysfunction are major causes of morbidity and mortality in hypertension. In the present study, we explored the beneficial therapeutic effect of endoplasmic ...reticulum (ER) stress inhibition on cardiac damage and vascular dysfunction in hypertension.
METHODS AND RESULTS—Mice were infused with angiotensin II (400 ng/kg per minute) with or without ER stress inhibitors (taurine-conjugated ursodeoxycholic acid and 4-phenylbutyric acid) for 2 weeks. Mice infused with angiotensin II displayed an increase in blood pressure, cardiac hypertrophy and fibrosis associated with enhanced collagen I content, transforming growth factor-β1 (TGF-β1) activity, and ER stress markers, which were blunted after ER stress inhibition. Hypertension induced ER stress in aorta and mesenteric resistance arteries (MRA), enhanced TGF-β1 activity in aorta but not in MRA, and reduced endothelial NO synthase phosphorylation and endothelium-dependent relaxation (EDR) in aorta and MRA. The inhibition of ER stress significantly reduced TGF-β1 activity, enhanced endothelial NO synthase phosphorylation, and improved EDR. The inhibition of TGF-β1 pathway improved EDR in aorta but not in MRA, whereas the reduction in reactive oxygen species levels ameliorated EDR in MRA only. Infusion of tunicamycin in control mice induced ER stress in aorta and MRA, and reduced EDR by a TGF-β1–dependent mechanism in aorta and reactive oxygen species–dependent mechanism in MRA.
CONCLUSION—ER stress inhibition reduces cardiac damage and improves vascular function in hypertension. Therefore, ER stress could be a potential target for cardiovascular diseases.
•Investigated INSL2/RXFP2 signaling using in vitro models.•DEHP, DBP and bisphenol A mixture based upon human amniotic fluid level.•DEHP, DBP and bisphenol A individually potentiate RXFP2 ...activity.•DEHP, DBP and bisphenol A mixture reduces the response to INSL3.•New mechanism of action for potential endocrine disrupting chemicals.
The presence of chemical pollutants in the environment can affect human health. Epidemiological and in vivo experimental studies reveal reprotoxic effects (undescended testis) of phthalates (diethylhexyl phthalate (DEHP), dibutyl phthalate (DBP)) and bisphenol A (BPA), resulting in particular of a decrease in INSL3 (Insulin-Like 3 peptide) production. This hormone is essential for normal testis development and acts on a G protein-coupled receptor: RXFP2.
The aim of this study was to evaluate the individual and combined impacts of DEHP, DBP, and BPA on human RXFP2 (hRXFP2) activity.
We used HEK293 cells transiently transfected with hRXFP2 and receptor activity was analyzed by measuring intracellular cAMP production. The mixture was established at concentrations reported in human amniotic fluid, for the three compounds.
Individually, DEHP, DBP and BPA increased the response to INSL3 by 19.3 to 27.5%. This potentiating effect was specific for RXFP2, because it was absent in the cells which did not express this receptor. On the other hand, and interestingly, the mixture of the three compounds reduced significantly the response to INSL3 by 12%, and the observed effects were opposite to those predicted, suggesting an antagonist effect.
Taken together, our results demonstrate for the first time that a mixture of phthalates and BPA present in human amniotic fluid disturbs the human RXFP2 function. Moreover, we demonstrate that mixture can produce potential antagonistic effects that are not displayed by the compounds, individually.
Cardiovascular diseases are a leading cause of mortality and disability worldwide. Hypertension, a major risk factor for these diseases, remains difficult to treat despite numerous drugs being ...available. In this issue of the JCI, Failer et al. show that the endogenous antiinflammatory agent developmental endothelial locus-1 (DEL-1) decreased blood pressure and cardiac and aortic hypertrophy in mouse models of hypertension through reduction in alpha.sub.vbeta.sub.3 integrin-dependent metalloproteinase activity and immune cell recruitment, leading to reduced production of proinflammatory cytokines in cardiovascular tissues. This study offers an alternative in the treatment of hypertension-mediated organ damage through the immunomodulatory effect of DEL-1.
Cardiovascular diseases are a leading cause of mortality and disability worldwide. Hypertension, a major risk factor for these diseases, remains difficult to treat despite numerous drugs being ...available. In this issue of theJCI, Failer et al. show that the endogenous antiinflammatory agent developmental endothelial locus-1 (DEL-1) decreased blood pressure and cardiac and aortic hypertrophy in mouse models of hypertension through reduction in avß3 integrin-dependent metalloproteinase activity and immune cell recruitment, leading to reduced production of proinflammatory cytokines in cardiovascular tissues. This study offers an alternative in the treatment of hypertension-mediated organ damage through the immunomodulatory effect of DEL-1.
Cardiovascular diseases (CVDs) are considered as a major cause of death worldwide. Therefore, identifying and developing therapeutic strategies to treat and reduce the prevalence of CVDs is a major ...medical challenge. Several drugs used for the treatment of CVDs, such as captopril, emerged from natural products, namely snake venoms. These venoms are complex mixtures of bioactive molecules, which, among other physiological networks, target the cardiovascular system, leading to them being considered in the development and design of new drugs. In this review, we describe some snake venom molecules targeting the cardiovascular system such as phospholipase A2 (PLA2), natriuretic peptides (NPs), bradykinin-potentiating peptides (BPPs), cysteine-rich secretory proteins (CRISPs), disintegrins, fibrinolytic enzymes, and three-finger toxins (3FTXs). In addition, their molecular targets, and mechanisms of action-vasorelaxation, inhibition of platelet aggregation, cardioprotective activities-are discussed. The dissection of their biological effects at the molecular scale give insights for the development of future snake venom-derived drugs.
Mycobacterium ulcerans, the etiological agent of Buruli ulcer, causes extensive skin lesions, which despite their severity are not accompanied by pain. It was previously thought that this remarkable ...analgesia is ensured by direct nerve cell destruction. We demonstrate here that M. ulcerans-induced hypoesthesia is instead achieved through a specific neurological pathway triggered by the secreted mycobacterial polyketide mycolactone. We decipher this pathway at the molecular level, showing that mycolactone elicits signaling through type 2 angiotensin II receptors (AT2Rs), leading to potassium-dependent hyperpolarization of neurons. We further validate the physiological relevance of this mechanism with in vivo studies of pain sensitivity in mice infected with M. ulcerans, following the disruption of the identified pathway. Our findings shed new light on molecular mechanisms evolved by natural systems for the induction of very effective analgesia, opening up the prospect of new families of analgesics derived from such systems.
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•Buruli ulcer caused by Mycobacterium ulcerans is characterized by painless lesions•Mycolactone produced by M. ulcerans induces hypoesthesia without nerve damage•Pathway characterization pinpoints AT2R receptors as targets for mycolactone•Model provides insight into implementation of analgesia in natural systems
The absence of pain in Buruli ulcer, despite extensive skin lesions, is ensured by the toxin mycolactone secreted by Mycobacterium ulcerans through the triggering of a specific angiotensin (AT2R) pathway.
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