Cristina Rabadan-Diehl

Vasopressinergic regulation of the hypothalamic-pituitary-adrenal axis : implications for stress adaptation

In addition to its role on water conservation, vasopressin (VP) regulates pituitary ACTH secretion by potentiating the stimulatory effects of corticotropin releasing hormone (CRH). The pituitary actions of VP are mediated by plasma membrane receptors of the V1b subtype, coupled to calcium-phospholipid signaling systems. VP is critical for adaptation of the hypothalamic-pituitary-adrenal (HPA) axis to stress as indicated by preferential expression of VP over CRH in parvocellular neurons of the hypothalamic paraventricular nucleus, and the upregulation of pituitary VP receptors during stress paradigms associated with corticotroph hyperresponsiveness. V1b receptor mRNA levels and coupling of the receptor to phospolipase C are stimulated by glucocorticoids, effects which may contribute to the refractoriness of VP-stimulated ACTH secretion to glucocorticoid feedback. The data suggest that vasopressinergic regulation of the HPA axis is critical for sustaining corticotroph responsiveness in the presence of high circulating glucocorticoid levels during chronic stress.

Report of the National Heart, Lung, and Blood Institute-National Institute of Diabetes and Digestive and Kidney Diseases Working Group on Cardiovascular Complications of Type 1 Diabetes Mellitus

Cardiovascular disease (CVD) constitutes the major cause of mortality and morbidity in both type 1 (T1D) and type 2 (T2D) diabetes patients. Although the microvascular complications of T1D are well studied, macrovascular CVD, its treatment, and link to diabetes have been investigated primarily in T2D patients. On April 27 and 28, 2003, the National Heart, Lung, and Blood Institute (NHLBI) and the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) sponsored a meeting to identify ways to close gaps in our knowledge about CVD in T1D to improve prevention and treatment. Participants were asked to: (1) Evaluate opportunities for studying the pathogenesis of CVD in T1D patients. Risk factors unique to these patients were of particular interest, as well as studies of the cause of CVD in T1D with respect to existing databases or cohorts and involving partnerships between basic and clinical investigators. (2) Evaluate opportunities for intervention studies to treat or prevent CVD in T1D. Because of practical obstacles (recruitment, duration, and cost of interventional studies with hard clinical end points), identification of reliable methods and markers that enable efficient intervention were a high priority. The meeting included 3 sessions: (1) current understanding of T1D and CVD; (2) opportunities to expand our understanding of the pathogenesis and clinical course of CVD in T1D; and (3) opportunities for intervention studies to reduce cardiovascular complications in T1D. This report summarizes the presentations made and concludes with recommendations drawn from the presentations and discussion among the participants. The epidemic of T2D in the United States has focused renewed attention on its complications. The complication causing greatest mortality and expense is CVD, responsible for 65% to 75% of deaths in the T2D population. T1D is comparatively uncommon and usually has its onset in younger populations. Although not associated with many of …

Vasopressinergic Regulation of the Hypothalamic Pituitary Adrenal Axis and Stress Adaptation

Vasopressin (VP) stimulates pituitary ACTH secretion through interaction with receptors of the V1b subtype (V1bR, V3R), located in the plasma membrane of the pituitary corticotroph, mainly by potentiating the stimulatory effects of corticotropin releasing hormone (CRH). Chronic stress paradigms associated with corticotroph hyperresponsiveness lead to preferential expression of hypothalamic VP over CRH and upregulation of pituitary V1bR, suggesting an important role for VP during adaptation of the hypothalamic–pituitary–adrenal (HPA) axis to stress. Vasopressinergic regulation of ACTH secretion depends on the number of V1bRs as well as coupling of the receptor to phospholipase C (PLC) in the pituitary. Regulation of V1bR gene transcription may involve a number of regulatory elements in the promoter region, of which a GAGA box was shown to be essential. Although V1bR gene transcription is necessary to maintain V1bR mRNA levels, the lack of correlation between VP binding and V1bR mRNA suggests that regulation of mRNA translation is a major regulatory step of the number of V1bRs. V1bR translation appears to be under tonic inhibition by upstream minicistrons and positive regulation through protein kinase C (PKC) activation of an internal ribosome entry site (IRES) in the 5′ untranslated region (5′UTR) of the mRNA. The data provide mechanisms by which regulation of hypothalamic VP and pituitary V1bR content contribute to controlling HPA axis activity during chronic stress.

Regulation of Pituitary Vasopressin Receptors during Chronic Stress: Relationship to Corticotroph Responsiveness

The relationship between vasopressin (VP) receptor levels in the anterior pituitary and VP‐stimulated ACTH release in vitro was studied in rats subjected to various chronic stress paradigms. The stress models used were water deprivation for 60 h and administration of 2% NaCI in the drinking water (both of which are associated with decreased pituitary ACTH responsiveness), and repeated i.p.hypertonic saline injections or repeated daily immobilization for 14 days (associated with increased ACTH responsiveness to novel stimuli). VP receptors were measured by binding of [3H]arginine‐VP to anterior pituitary membrane‐rich fractions, and ACTH responses to VP in collagenase dispersed anterior pituitary cells. In control rats, binding of [3H]AVP was saturable and high affinity, with a Kd of 0.45 ± 0.05 nM and a Bmax of 138.8 ± 8.1 fmol/mg. In pituitary membranes from stressed rats, binding affinity was unchanged, but Bmax changed according to the type of stress. While VP binding was markedly reduced after water deprivation and 2% saline (25% and 49%, respectively), it was significantly increased after repeated i.p. hypertonic saline injections and repeated immobilization (126% and 154% of controls, respectively). The changes in VP binding were associated to parallel changes in maximum VP‐stimulated ACTH production in vitro, with a 34% decrease in water deprived rats and a 25% increase in hypertonic saline injected rats. The potentiating effect of VP on corticotropin releasing hormone‐stimulated ACTH was also reduced in cells from water‐restricted rats, and increased in cells from rats given repeated injections of hypertonic saline. The data show a direct relationship between changes in corticotroph responsiveness and changes in pituitary VP receptors during chronic stress, suggesting that pituitary VP receptor regulation is involved in the adaptation of the HPA axis during chronic stress.

Regulation of pituitary corticotropin releasing hormone receptors.

Corticotropin releasing hormone (CRH) stimulates pituitary ACTH secretion through type-1 CRH (CRH1) receptors. Stimulation of the hypothalamic pituitary adrenal (HPA) axis as well as increased corticotroph responsiveness during stress and adrenalectomy are associated with marked pituitary CRH binding downregulation. The presence of CRH1 receptors in the pituitary are essential to maintain ACTH secretion. Downregulation of CRH binding is associated with normal or elevated levels of CRH1 receptor mRNA and this may contribute to the maintainence of permissive levels of CRH1 receptors in the pituitary. Injection of either CRH or glucocorticoids in rats in vivo induces CRH binding and CRH1 receptor mRNA downregulation, whereas their simultaneous administration causes only transient CRH1 receptor mRNA loss. Vasopressin increases CRH1 receptor mRNA levels. This suggest that interactions between CRH, vasopressin and glucocorticoids accounts for CRH1 receptor mRNA upregulation during stress. The lack of correlation between CRH binding and CRH1 receptor mRNA indicates that the major sites for pituitary CRH1 receptor regulation are at the post-transcriptional level.

Regulation of Pituitary Vasopressin V1b Receptor mRNA during Stress in the Rat

Previous studies have shown a parallel relationship between pituitary vasopressin (VP) receptor content and responsiveness of the corticotroph during chronic stress. The regulation of pituitary VP receptors was further studied by analysis of V1b VP receptor mRNA levels in pituitaries of rats subjected to chronic immobilization, i.p. hypertonic saline injection (physical stress paradigms associated with increased pituitary responsiveness), and water deprivation, or to 2% saline in the drinking water (osmotic stress paradigms associated with decreased pituitary responsiveness). Northern blot hybridization with a 363 bp 32P‐labelled fragment of the rV1b receptor cDNA coding sequence revealed two bands of about 3.7 and 3.2 Kb, whereas a probe directed to the 5′ untranslated region recognized only the 3.7 Kb band. Repeated i.p. hypertonic saline injection, 3 times in 24 h at 8 h intervals, or daily for 8 days, increased the intensity of the 3.7 Kb band by 155 ± 17.5% (P<0.01) and 118 ± 14.6% (P<0.01), respectively, while the 3.2Kb band increased by 122 ± 39.3% (P<0.01) only after 3 times injection. Smaller increases of 39 ± 11 and 33 ± 9% (P<0.05) in the 3.7 Kb band were found after repeated immobilization 3 times in 24 h and 2 h for for 8 days respectively. In situ hybridization studies confirmed significant increases (P<0.05) in V1b receptor mRNA levels after 8 and 14 days repeated immobilization (63 ± 19% and 83 ± 10%) or i.p. hypertonic saline injection (110 ± 13% and 73 ± 20%). In response to acute stress, V1b receptor mRNA increased by 77 ± 5% (3.7 Kb band) after 4 h immobilization for 1 h, whereas both bands were reduced by 49 ± 5% and 45 ± 5%, 4 h after a single i.p. hypertonic saline injection. The decrease in V1b receptor mRNA following a single i.p. hypertonic saline injection was prevented by pretreatment with a V1 receptor antagonist, suggesting that increased VP secretion may account for this effect. In spite of the decrease in V1 b receptor mRNA following i.p. hypertonic saline injection, VP binding in pituitary membrane rich fractions, and VP‐stimulated inositol phosphate formation in quartered hemipituitaries were increased by 24 and 39%, respectively. V1b receptor mRNA levels were unchanged or decreased following prolonged osmotic stimulation.

Early-life prevention of non-communicable diseases

Non-communicable diseases (NCDs) are major causes of death worldwide and underlie almost two-thirds of all global deaths.1 Although all countries face epidemics of these diseases, low-income and middle-income countries, and the poorest and most vulnerable populations within them, are affected the most. There is a global imperative to create and implement effective prevention strategies, because the future costs of diagnosis and treatment are likely to be unaffordable. At the UN High-Level Meeting on the Prevention and Control of Non-Communicable Diseases, held in New York, USA, in September, 2011, the so-called four by four strategy for NCD prevention was proposed. Prevention efforts for the priority NCDs discussed at the meeting (diabetes, cardiovascular disease, cancer, and chronic obstructive pulmonary disease) focus on four, mainly adult, risk factors: poor diet, physical inactivity, tobacco use, and alcohol consumption. Although paragraphs 26 and 28 of the UN Political Declaration refer to the roles of prenatal nutrition, maternal diseases, and household air pollution on NCD risk in later life, these paragraphs only partially describe the full scope of the problem and opportunities for intervention. As scientific knowledge emerges on the role of both nutritional factors and exposures to environmental chemicals in the developmental origins of health and disease, evidence suggests that much more attention is needed on early-life interventions, optimisation of nutrition, and reduction of toxic exposures to curtail the increasing prevalence of NCDs. The present state of the science on the developmental origins of health and disease and NCDs was discussed at the Prenatal Programming and Toxicity III conference, Environmental Stressors in the Developmental Origins of Disease: Evidence and Mechanisms, held in Paris, France in May, 2012, and at a symposium just before the conference.2 Studies in human beings have shown that nutritional deprivation and maternal metabolic status (eg, diabetes) in early intrauterine life increase the risk of metabolic disorders and cardiovascular disease in adulthood.3,4 These effects occur not only in settings of extreme deprivation, but also throughout the normal range of population weights at birth and in early childhood.3 Investigators have also reported associations between in-utero exposures and childhood diseases, including type 2 diabetes.5 In-utero and early-life exposures to environmental toxicants, ranging from heavy metals to endocrine-disrupting chemicals, affect adult metabolism, immune system function, neurodevelopment, and reproductive function.2 Although causal relations have not yet been established, the new science of epigenetics offers insight into mechanisms of early life predisposition to adult disease risk. During development, epigenetic marks, such as DNA methylation, histone modifications, and noncoding RNA expression, undergo substantial changes. These changes affect genes that are essential for both early life development and later life physiological functions. Epigenetic modifications are stable during cell division and can be transmitted transgenerationally.6 An increasing amount of evidence suggests that developmental exposure to nutritional imbalance or environmental contaminants—including metals, pesticides, persistent organic pollutants, and chemicals in drinking water, such as triethyltin, chloroform, and trihalomethanes—can affect epigenetic changes, thus suggesting a mechanism for their effects on adult health.7,8 Similarly, prenatal exposure to air pollutants has been associated with epigenetic changes and subsequent effects on children’s respiratory health.9 Knowledge that in-utero and early childhood experiences affect the risk of NCD development provides an opportunity to target interventions at the time when they have the greatest effect. Because these exposures are not controlled directly by the individual, especially when the exposures might have occurred to the individual’s parents or grandparents, early-life interventions can reduce the perception of blame that the individual’s own lifestyle has caused his or her disease. This notion has policy implications, because the prevailing viewpoint often assumes that NCDs are mainly a matter of individual responsibility, thus obviating societal and governmental responsibility. Substantial reductions of NCD risks could be achieved through the use of existing maternal–child health platforms to educate mothers about both nutritional and environmental exposures and to integrate the health promotion and disease prevention agendas within social and economic development efforts. For example, the Millennium Development Goals (MDGs) address not only maternal and child health problems, but also poverty and malnutrition, sex inequality, and lack of education, all of which are notable drivers of social disadvantage in low-income and middle-income countries and are underlying causes of NCDs.10,11 Poverty alleviation, sustainable food production, and reductions in exposures to toxic chemicals are all key themes emerging from the Rio+20 UN Conference on Sustainable Development12 held in Rio de Janeiro, Brazil, in June, 2012, and the development of Sustainable Development Goals (SDGs) and appropriate environmental, nutritional, and health indicators provides another opportunity to incorporate NCD prevention into broader, multisector programmes. The integration of NCD prevention with the attainment of the MDGs and SDGs could leverage major worldwide investments in health and development.

HIV and noncommunicable cardiovascular and pulmonary diseases in low- and middle-income countries in the ART era: what we know and best directions for future research.

Abstract:With the advent of effective antiretroviral therapy (ART), HIV is becoming a chronic disease. HIV-seropositive (+) patients on ART can expect to live longer and, as a result, they are at risk of developing chronic noncommunicable diseases related to factors, such as aging, lifestyle, long-term HIV infection, and the potential adverse effects of ART. Although data are incomplete, evidence suggests that even in low- and middle-income countries (LMICs), chronic cardiovascular and pulmonary diseases are increasing in HIV-positive patients. This review summarizes evidence-linking HIV infection to the most commonly cited chronic cardiovascular and pulmonary conditions in LMICs: heart failure, hypertension, coronary artery disease/myocardial infarction, stroke, obstructive lung diseases, and pulmonary arterial hypertension. We describe the observed epidemiology of these conditions, factors affecting expression in LMICs, and key populations that may be at higher risk (ie, illicit drug users and children), and finally, we suggest that strategic areas of research and training intended to counter these conditions effectively. As access to ART in LMICs increases, long-term outcomes among HIV-positive persons will increasingly be determined by a range of associated chronic cardiovascular and pulmonary complications. Actions taken now to identify those conditions that contribute to long-term morbidity and mortality optimize early recognition and diagnosis and implement effective prevention strategies and/or disease interventions are likely to have the greatest impact on limiting cardiovascular and pulmonary disease comorbidity and improving population health among HIV-positive patients in LMICs.

Regulation of vasopressin V1b receptors in the anterior pituitary gland of the rat

Vasopressin secreted by parvocellular neurones of the hypothalamic paraventricular nucleus modulates pituitary adrenocorticotrophic hormone (ACTH) secretion by acting upon vasopressin V1b type receptors in the pituitary corticotroph coupled to phospholipase C. Regulation of V1b receptors contributes to the adaptation of the hypothalamic‐pituitary‐adrenal (HPA) axis to stress, as evidenced by the correlation between vasopressin receptor number and pituitary ACTH responsiveness. V1b receptor upregulation during chronic stress is associated with elevated circulating glucocorticoids and vasopressin expression in parvocellular neurones, suggesting that these factors control V1b receptor expression. Removal of circulating glucocorticoids by adrenalectomy causes sustained vasopressin receptor downregulation, but reduces V1b receptor mRNA only transiently. The latter effect is not mediated by increased corticotrophin‐releasing hormone (CRH) and vasopressin release, since it is not prevented by lesions of the hypothalamic paraventricular nucleus. Adrenalectomy causes sustained V1b receptor loss in Brattleboro rats, which lack hypothalamic vasopressin, suggesting that vasopressin mediates V1b receptor mRNA recovery. Exogenous glucocorticoid administration downregulates pituitary vasopressin binding but increases V1b receptor mRNA and facilitates coupling of the receptor to phospholipase C, effects which may contribute to the refractoriness of vasopressin actions to glucocorticoid feedback. The lack of parallelism between changes in pituitary vasopressin binding and V1b receptor mRNA levels during manipulation of the HPA axis indicates that V1b receptor content depends on post‐transcriptional mechanisms rather than steady‐state V1b receptor mRNA levels. These studies suggest that interaction between glucocorticoids and vasopressin plays an important role in regulating V1b receptor mRNA expression during alterations of the HPA axis. In addition, the recent characterization of a major part of the V1b receptor gene provides a basis for studying the molecular mechanisms regulating the V1b receptor.

Household Air Pollution from Solid Fuel Use: Evidence for Links to CVD

More than 3 billion people worldwide continue to depend on solid fuels such as wood, dung, or crop residues for cooking and heating [1]. Use of these fuels in traditional stoves or open fires results in very high levels of household air pollution (HAP), with women and young children bearing a disproportionate burden of the health effects. The World Health Organization estimates that indoor air pollution from solid fuel use accounts for more than 1.9 million (3.3%) of annual deaths, making household air pollution the largest environmental contributor to mortality in the world, even greater than unsafe water and sanitation [2]. Evidence suggests that HAP is associated with increased susceptibility to lung diseases [3], and there is much interest in fuel-efficient, low-emission cook stoves as a way to improve respiratory health and decrease mortality in resource-poor countries. Fewer studies have evaluated the effects of HAP on the cardiovascular system, and only 1 study has examined associations between solid fuel use and self-reported diagnosis of cardiovascular diseases (CVD) [4]. However, combustion-generated aerosols from other sources, and especially fine particulate matter, are considered important causes of CVD and mortality [5]. Whereas CVD mortality has substantially declined in the developed world, there is an emerging CVD epidemic in lowandmiddle-income countries