RESUMO
The essential role of the Y chromosome in male sex determination has largely overshadowed the possibility that it may exert other biologic roles. Here, we show that Y-chromosome lineage is a strong determinant of perivascular and renal T-cell infiltration in the stroke-prone spontaneously hypertensive rat, which, in turn, may influence vascular function and blood pressure (BP). We also show, for the first time to our knowledge, that augmented perivascular T-cell levels can directly instigate vascular dysfunction, and that the production of reactive oxygen species that stimulate cyclo-oxygenase underlies this. We thus provide strong evidence for the consideration of Y-chromosome lineage in the diagnosis and treatment of male hypertension, and point to the modulation of cardiovascular organ T-cell infiltration as a possible mechanism that underpins Y- chromosome regulation of BP.-Khan, S. I., Andrews, K. L., Jackson, K. L., Memon, B., Jefferis, A.-M., Lee, M. K. S., Diep, H., Wei, Z., Drummond, G. R., Head, G. A., Jennings, G. L., Murphy, A. J., Vinh, A., Sampson, A. K., Chin-Dusting, J. P. F. Y-chromosome lineage determines cardiovascular organ T-cell infiltration in the stroke-prone spontaneously hypertensive rat.
Assuntos
Pressão Sanguínea , Hipertensão/metabolismo , Hipertensão/fisiopatologia , Linfócitos T/metabolismo , Cromossomo Y/metabolismo , Animais , Hipertensão/genética , Masculino , Ratos , Ratos Endogâmicos SHR , Ratos Transgênicos , Linfócitos T/patologia , Cromossomo Y/genéticaRESUMO
It is now becomingly increasingly evident that the functions of the mammalian Y chromosome are not circumscribed to the induction of male sex. While animal studies have shown variations in the Y are strongly accountable for blood pressure (BP), this is yet to be confirmed in humans. We have recently shown modulation of adaptive immunity to be a significant mechanism underpinning Y-chromosome-dependent differences in BP in consomic strains. This is paralleled by studies in man showing Y chromosome haplogroup is a significant predictor for coronary artery disease through influencing pathways of immunity. Furthermore, recent studies in mice and humans have shown that Y chromosome lineage determines susceptibility to autoimmune disease. Here we review the evidence in animals and humans that Y chromosome lineage influences hypertension and cardiovascular disease risk, with a novel focus on pathways of immunity as a significant pathway involved.
Assuntos
Pressão Sanguínea/genética , Doenças Cardiovasculares/genética , Imunidade Inata/genética , Cromossomo Y/genética , Animais , Doenças Cardiovasculares/imunologia , HumanosRESUMO
Vascular dysfunction is a hallmark of hypertension and the strongest risk factor to date for coronary artery disease. As Y chromosome lineage has emerged as one of the strongest genetic predictors of cardiovascular disease risk to date, we investigated if Y chromosome lineage modulated this important facet in the stroke-prone spontaneously hypertensive rat (SHRSP) using consomic strains. Here, we show that vascular dysfunction in the SHRSP is attributable to differential cyclooxygenase (COX) activity with nitric oxide (NO) levels playing a less significant role. Measurement of prostacyclin, the most abundant product of COX in the vasculature, confirmed the augmented COX activity in the SHRSP aorta. This was accompanied by functional impairment of the vasodilatory prostacyclin (IP) receptor, while inhibition of the thromboxane (TP) receptor significantly ameliorated vascular dysfunction in the SHRSP, suggesting this is the downstream target responsible for constrictor prostanoid activity. Importantly, Y chromosome lineage was shown to modulate vascular function in the SHRSP through influencing COX activity, prostacyclin levels and IP dysfunction. Vascular dysfunction in the renal and intrarenal arteries was also found to be prostanoid and Y chromosome dependent. Interestingly, despite no apparent differences in agonist-stimulated NO levels, basal NO levels were compromised in the SHRSP aorta, which was also Y chromosome dependent. Thus, in contrast with the widely held view that COX inhibition is deleterious for the vasculature due to inhibition of the vasodilator prostacyclin, we show that COX inhibition abolishes vascular dysfunction in three distinct vascular beds, with IP dysfunction likely being a key mechanism underlying this effect. We also delineate a novel role for Y chromosome lineage in regulating vascular function through modulation of COX and basal NO levels.
Assuntos
Aorta/fisiopatologia , Hipertensão/fisiopatologia , Prostaglandinas/metabolismo , Acidente Vascular Cerebral/fisiopatologia , Cromossomo Y , Acetilcolina/farmacologia , Animais , Aorta/metabolismo , Endotélio Vascular/metabolismo , Endotélio Vascular/fisiopatologia , Hipertensão/genética , Masculino , Óxido Nítrico/metabolismo , Prostaglandina-Endoperóxido Sintases/metabolismo , Ratos Endogâmicos SHR , Ratos Endogâmicos WKY , Acidente Vascular Cerebral/genética , Vasodilatação/efeitos dos fármacos , Vasodilatadores/farmacologiaRESUMO
Nitroxyl anion (HNO) donors are currently being assessed for their therapeutic utility in several cardiovascular disorders including heart failure. Here, we examine their effect on factors that precede atherosclerosis including endothelial cell and monocyte activation, leucocyte adhesion to the endothelium and macrophage polarization. Similar to the NO donor glyceryl trinitrate (GTN), the HNO donors Angeli's salt (AS) and isopropylamine NONOate (IPA/NO) decreased leucocyte adhesion to activated human umbilical vein endothelial cells (HUVECs) and mouse isolated aorta. This reduction in adhesion was accompanied by a reduction in intercellular adhesion molecule-1 (ICAM-1) and the cytokines monocyte chemoattractant protein 1 (MCP-1) and interleukin 6 (IL-6) which was inhibitor of nuclear factor κB (NFκB) α (IκBα)- and subsequently NFκB-dependent. Intriguingly, the effects of AS on leucocyte adhesion, like those on vasodilation, were found to not be susceptible to pharmacological tolerance, unlike those observed with GTN. As well, HNO reduces monocyte activation and promotes polarization of M2 macrophages. Taken together, our data demonstrate that HNO donors can reduce factors that are associated with and which precede atherosclerosis and may thus be useful therapeutically. Furthermore, since the effects of the HNO donors were not subject to tolerance, this confers an additional advantage over NO donors.
Assuntos
Aterosclerose/tratamento farmacológico , Polaridade Celular/efeitos dos fármacos , Células Endoteliais da Veia Umbilical Humana/efeitos dos fármacos , Macrófagos/efeitos dos fármacos , Monócitos/citologia , Monócitos/efeitos dos fármacos , Óxidos de Nitrogênio/administração & dosagem , Animais , Aorta/efeitos dos fármacos , Aorta/imunologia , Aorta/fisiopatologia , Aterosclerose/imunologia , Aterosclerose/fisiopatologia , Quimiocina CCL2/imunologia , Células Endoteliais da Veia Umbilical Humana/citologia , Células Endoteliais da Veia Umbilical Humana/imunologia , Humanos , Molécula 1 de Adesão Intercelular/imunologia , Interleucina-6/imunologia , Macrófagos/citologia , Macrófagos/imunologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Monócitos/imunologiaRESUMO
Many studies report sexual dimorphism in the fetal programming of adult disease. We hypothesized that there would be differences in the age-related decline in renal function between male and female intrauterine growth-restricted rats. Early-life growth restriction was induced in rat offspring by administering a low-protein diet (LPD; 8.7% casein) to dams during pregnancy and lactation. Control dams were fed a normal-protein diet (NPD; 20% casein). Mean arterial pressure (MAP) and renal structure and function were assessed in 32- and 100-wk-old offspring. Mesenteric artery function was examined at 100 wk using myography. At 3 days of age, body weight was â¼24% lower (P < 0.0001) in LPD offspring; this difference was still apparent at 32 wk but not at 100 wk of age. MAP was not different between the male NPD and LPD groups at either age. However, MAP was greater in LPD females compared with NPD females at 100 wk of age (â¼10 mmHg; P < 0.001). Glomerular filtration rate declined with age in the NPD male, LPD male and LPD female offspring (â¼45%, all P < 0.05), but not in NPD female offspring. Mesenteric arteries in the aged LPD females had reduced sensitivity to nitric oxide donors compared with their NPD counterparts, suggesting that vascular dysfunction may contribute to the increased risk of disease in aged females. In conclusion, females growth-restricted in early life were no longer protected from an age-related decline in renal and arterial function, and this was associated with increased arterial pressure without evidence of renal structural damage.
Assuntos
Envelhecimento , Pressão Arterial , Retardo do Crescimento Fetal/fisiopatologia , Rim/fisiopatologia , Artérias Mesentéricas/fisiopatologia , Efeitos Tardios da Exposição Pré-Natal/fisiopatologia , Animais , Feminino , Taxa de Filtração Glomerular , Masculino , Gravidez , Ratos , Ratos Endogâmicos WKY , Caracteres Sexuais , VasoconstriçãoRESUMO
Sex differences exist in the regulation of arterial pressure and renal function by the renin-angiotensin system (RAS). This may in part stem from a differential balance in the pressor and depressor arms of the RAS. In males, the ACE/AngII/AT(1)R pathways are enhanced, whereas, in females, the balance is shifted towards the ACE2/Ang(1-7)/MasR and AT(2)R pathways. Evidence clearly demonstrates that premenopausal women, as compared to aged-matched men, are protected from renal and cardiovascular disease, and this differential balance of the RAS between the sexes likely contributes. With aging, this cardiovascular protection in women is lost and this may be related to loss of estrogen postmenopause but the possible contribution of other sex hormones needs to be further examined. Restoration of these RAS depressor pathways in older women, or up-regulation of these in males, represents a therapeutic target that is worth pursuing.
Assuntos
Sistema Renina-Angiotensina/fisiologia , Animais , Pressão Sanguínea/fisiologia , Estrogênios/fisiologia , Feminino , Genes sry/fisiologia , Humanos , Masculino , Polimorfismo Genético/fisiologia , Proto-Oncogene Mas , Receptores de Angiotensina/fisiologia , Renina/sangue , Cromossomos Sexuais/fisiologia , Fatores Sexuais , Transdução de Sinais/fisiologia , Testosterona/fisiologiaRESUMO
The complex role of the renin-angiotensin-system (RAS) in arterial pressure regulation has been well documented. Recently, we demonstrated that chronic low-dose angiotensin II (ANG II) infusion decreases arterial pressure in female rats via an AT(2)R-mediated mechanism. Estrogen can differentially regulate components of the RAS and is known to influence arterial pressure regulation. We hypothesized that AT(2)R-mediated depressor effects evident in females were estrogen dependent and thus would be abolished by ovariectomy and restored by estrogen replacement. Female Sprague-Dawley rats underwent ovariectomy or sham surgery and were treated with 17ß-estradiol or placebo. Mean arterial pressure (MAP) was measured via telemetry in response to a 2-wk infusion of ANG II (50 ng·kg(-1)·min(-1) sc) or saline. MAP significantly decreased in females treated with ANG II (-10 ± 2 mmHg), a response that was abolished by ovariectomy (+4 ± 2 mmHg) and restored with estrogen replacement (-6 ± 2 mmHg). Cardiac and renal gene expression of components of the RAS was differentially regulated by estrogen, such that overall, estrogen shifted the balance of the RAS toward the vasodilatory axis. In conclusion, estrogen-dependent mechanisms offset the vasopressor actions of ANG II by enhancing RAS vasodilator pathways in females. This highlights the potential for these vasodilator pathways as therapeutic targets, particularly in women.
Assuntos
Angiotensina II/farmacologia , Pressão Sanguínea/efeitos dos fármacos , Pressão Sanguínea/fisiologia , Estrogênios/fisiologia , Ovariectomia , Vasoconstritores/farmacologia , Angiotensina I/sangue , Angiotensina II/administração & dosagem , Enzima de Conversão de Angiotensina 2 , Animais , Relação Dose-Resposta a Droga , Estradiol/farmacologia , Estrogênios/deficiência , Feminino , Infusões Subcutâneas , Rim/metabolismo , Modelos Animais , Fragmentos de Peptídeos/sangue , Peptidil Dipeptidase A/metabolismo , Ratos , Ratos Sprague-Dawley , Receptor Tipo 2 de Angiotensina/metabolismo , Sistema Renina-Angiotensina/efeitos dos fármacos , Sistema Renina-Angiotensina/fisiologia , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/fisiologia , Vasoconstritores/administração & dosagemRESUMO
This article describes and illustrates a novel method of microarray data analysis that couples model-based clustering and binary classification to form clusters of `response-relevant' genes; that is, genes that are informative when discriminating between the different values of the response. Predictions are subsequently made using an appropriate statistical summary of each gene cluster, which we call the `meta-covariate' representation of the cluster, in a probit regression model. We first illustrate this method by analysing a leukaemia expression dataset, before focusing closely on the meta-covariate analysis of a renal gene expression dataset in a rat model of salt-sensitive hypertension. We explore the biological insights provided by our analysis of these data. In particular, we identify a highly influential cluster of 13 genes--including three transcription factors (Arntl, Bhlhe41 and Npas2)-that is implicated as being protective against hypertension in response to increased dietary sodium. Functional and canonical pathway analysis of this cluster using Ingenuity Pathway Analysis implicated transcriptional activation and circadian rhythm signalling, respectively. Although we illustrate our method using only expression data, the method is applicable to any high-dimensional datasets. Expression data are available at ArrayExpress (accession number E-MEXP-2514) and code is available at http://www.dcs.gla.ac.uk/inference/metacovariateanalysis/.
Assuntos
Perfilação da Expressão Gênica/métodos , Análise de Sequência com Séries de Oligonucleotídeos/métodos , Animais , Ritmo Circadiano/genética , Análise por Conglomerados , Redes Reguladoras de Genes , Humanos , Hipertensão/genética , Hipertensão/metabolismo , Rim/metabolismo , Leucemia/genética , Leucemia/metabolismo , Ratos , Análise de RegressãoRESUMO
The aetiology and progression of hypertension involves various endogenous systems, such as the renin angiotensin system, the sympathetic nervous system, and endothelial dysfunction. Recent data suggest that vascular inflammation may also play a key role in the pathogenesis of hypertension. This study sought to determine whether high intraluminal pressure results in vascular inflammation. Leukocyte adhesion was assessed in rat carotid arteries exposed to 1 h of high intraluminal pressure. The effect of intraluminal pressure on signaling mechanisms including reactive oxygen species production (ROS), arginase expression, and NFĸB translocation was monitored. 1 h exposure to high intraluminal pressure (120 mmHg) resulted in increased leukocyte adhesion and inflammatory gene expression in rat carotid arteries. High intraluminal pressure also resulted in a downstream signaling cascade of ROS production, arginase expression, and NFĸB translocation. This process was found to be angiotensin II-independent and mediated by the mechanosensor caveolae, as caveolin-1 (Cav1)-deficient endothelial cells and mice were protected from pressure-induced vascular inflammatory signaling and leukocyte adhesion. Cav1 deficiency also resulted in a reduction in pressure-induced glomerular macrophage infiltration in vivo. These findings demonstrate Cav1 is an important mechanosensor in pressure-induced vascular and renal inflammation.
Assuntos
Vasos Sanguíneos/metabolismo , Vasos Sanguíneos/patologia , Caveolina 1/metabolismo , Inflamação/metabolismo , Inflamação/patologia , Bloqueadores do Receptor Tipo 1 de Angiotensina II/farmacologia , Animais , Pressão Sanguínea , Cavéolas/metabolismo , Adesão Celular , Endotélio Vascular/metabolismo , Endotélio Vascular/patologia , Endotélio Vascular/ultraestrutura , Hipertensão/patologia , Rim/patologia , Leucócitos/patologia , Macrófagos/patologia , Camundongos Endogâmicos C57BL , Modelos Biológicos , NF-kappa B/metabolismo , Norepinefrina , Ratos , Espécies Reativas de Oxigênio/metabolismo , Receptor Tipo 1 de Angiotensina/metabolismoRESUMO
BACKGROUND: Migrant workers have been identified in Europe, North America, Asia and Australia as a particularly vulnerable working population with a higher risk of work-related injury and mortality compared to non-migrant workers. Lack of English language proficiency is associated with an increased risk of work-related injury. Whether lack of English proficiency influences post-injury recovery or return to work outcomes remains unknown. OBJECTIVE: Using administrative data from a population based workers' compensation dataset in the state of Victoria, Australia, we aimed to examine work-related injury rates, worker characteristics and compensation outcomes in workers who were not proficient in English. We hypothesized that the use of an interpreter service would be associated with a poorer post-injury recovery profile and worse return to work outcomes. METHODS: WorkSafe Victoria accepted non-fatal claims for injuries and illnesses reported between January 1, 2003, and December 31, 2012 by workers aged 15 to 74 (nâ=â402, 828 claims) were analysed. Consistent with prior research, we selected "use of an interpreter service" as the indicator of English language proficiency. The total and categorical compensable cost of recovery was used as recovery outcomes. RESULTS: Of these claims, 16,286 (4%) involved the use of an interpreter service (LOTE workers). Our analysis revealed that Victorian injured LOTE workers have significantly different demographic, occupational and injury characteristics compared to non-LOTE injured workers. Furthermore, we present novel evidence that LOTE status was associated with poorer long-term injury outcomes, observed as a greater healthcare utilisation and larger paid income benefits, after controlling for occupation, employment status and injury type compared to non-LOTE injured workers. CONCLUSIONS: These data suggest that English language proficiency is associated not only with the risk of work-related injury but also to the long-term recovery outcomes. We conclude that despite access to language interpreter services, injured LOTE workers experience English language proficiency dependent, and injury severity independent, recovery barriers which need to be overcome to improve long term recovery outcomes.
Assuntos
Idioma , Traumatismos Ocupacionais , Europa (Continente) , Humanos , América do Norte , Traumatismos Ocupacionais/epidemiologia , Vitória/epidemiologia , Indenização aos TrabalhadoresRESUMO
1. The aim of this study was to investigate the effect of chronic angiotensin II (AngII) infusion on the circadian rhythms of arterial blood pressure, heart rate (HR) and locomotor activity (ACT) in male and female rats. 2. Radiotelemetry probes were implanted into the aorta in male and female rats and allowed 10 days for recovery. Control levels for mean arterial pressure (MAP), HR and ACT were recorded for 3 days, then AngII (400 ng/kg per min s.c. via osmotic minipump) or vehicle (saline) was infused for 10 days (n = 6 per group). Further recordings of MAP, HR and ACT were made during days 8, 9 and 10 of the infusion period. 3. In response to AngII infusion, night and day-time MAP increased significantly in female (18 +/- 2 mmHg; 28 +/- 7 mmHg) and male (27 +/- 4 mmHg; 30 +/- 3 mmHg) rats, respectively. The degree of elevation in MAP in response to AngII was attenuated in the females during the night period (P(sex) < 0.05) but not the day (P(sex) = 0.2). Control night-day differences in MAP, HR and ACT averaged 7 +/- 1 mmHg, 58 +/- 5 b.p.m. and 30 +/- 4 units in the female and 6 +/- 1 mmHg, 43 +/- 3 b.p.m. (P(sex) < 0.05) and 14 +/- 2 units (P(sex) < 0.05) in male rats, respectively. AngII infusion disrupted MAP circadian rhythm in female (-4 +/- 2 mmHg) and male rats (1 +/- 2 mmHg; P(treat) < 0.01), but did not affect heart rate or locomotor activity. 4. In conclusion, sex differences in the circadian rhythm of heart rate and locomotor activity, but not arterial pressure exist under basal conditions. Circulating AngII modulated the circadian rhythm of MAP in female and male rats but not heart rate or locomotor activity. These findings have important implications for our understanding of circadian blood pressure rhythms in states of activation of the renin angiotensin system.
Assuntos
Angiotensina II/administração & dosagem , Angiotensina II/farmacologia , Pressão Sanguínea/efeitos dos fármacos , Ritmo Circadiano/efeitos dos fármacos , Caracteres Sexuais , Animais , Esquema de Medicação , Feminino , Masculino , Atividade Motora/efeitos dos fármacos , Ratos , Ratos Sprague-DawleyRESUMO
BACKGROUND AND PURPOSE: Angiotensin AT2 receptors are upregulated in disease states such as atherosclerosis and blockade of the AT2 receptors exacerbates plaque formation. Direct stimulation of these receptors is anti-atherogenic but the mechanisms and pathways involved remain unknown. We examined the effect of direct AT2 receptor stimulation with Compound 21 (C21) on the leukocyte adhesion cascade in vitro, right through to plaque formation in vivo. EXPERIMENTAL APPROACH: Effects of C21 on TNFα-induced inflammation were assessed in human umbilical vein endothelial cells (HUVECs), activation of monocytes, polarisation of monocyte-derived macrophages and in intact mouse aortae. KEY RESULTS: C21 attenuated TNFα-induced: monocyte adhesion to cultured HUVECs, adhesion molecule expression and abolished TNFα-induced ROS production. TNFα-induced NFκB translocation from the cytoplasm to the nucleus, essential for cytokine production, was prevented by C21. C21 did not influence monocyte activation or macrophage polarisation but did reduce TNFα and IL-6 mRNA expression in M1 macrophages. The anti-inflammatory effects of C21 were abolished by an AT2 receptor antagonist confirming that the effects of C21 were AT2 receptor-mediated. Also, leukocyte adhesion and cytokine gene expression, induced by high-fat diet (HFD), was attenuated in ApoE(-/-) mice treated with C21. Plaque size and stability were improved with C21 treatment with increased smooth muscle cell composition and decreased lipid size, compared with HFD-saline treated mice. CONCLUSION AND IMPLICATIONS: C21 prevented TNFα-induced and HFD-induced vascular inflammation in vitro and in vivo. Our data provide strong evidence that the anti-atherosclerotic actions of C21 were due to vascular anti-inflammatory effects, mediated by AT2 receptors.
Assuntos
Células Endoteliais da Veia Umbilical Humana/efeitos dos fármacos , Inflamação/tratamento farmacológico , Leucócitos/efeitos dos fármacos , Receptor Tipo 2 de Angiotensina/agonistas , Sulfonamidas/farmacologia , Tiofenos/farmacologia , Animais , Apolipoproteínas E/deficiência , Apolipoproteínas E/metabolismo , Adesão Celular/efeitos dos fármacos , Células Cultivadas , Células Endoteliais da Veia Umbilical Humana/metabolismo , Células Endoteliais da Veia Umbilical Humana/patologia , Humanos , Inflamação/metabolismo , Inflamação/patologia , Leucócitos/citologia , Leucócitos/metabolismo , Masculino , Camundongos , Camundongos Knockout , Espécies Reativas de Oxigênio/metabolismo , Transdução de Sinais/efeitos dos fármacos , Sulfonamidas/química , Tiofenos/químicaRESUMO
BACKGROUND: The genetic contribution to salt-sensitivity in hypertension remains unclear. We have previously identified a quantitative trait locus on chromosome 2 in stroke-prone spontaneously hypertensive rats (SHRSPs) responsible for an increase in SBP in response to a salt challenge. This response is blunted in the congenic SHRSP strain with the Wistar-Kyoto (WKY) chromosome 2 region (10âcM) introgressed (SP.WKYGla2k). We aimed to discover the mechanisms that underlie the effects of this region on salt-handling in the SHRSP strain. METHOD: Renal and adreno-cortical function were compared in the WKY, SHRSP and the congenic SP.WKYGla2k strains. RESULTS: In response to the salt challenge, all strains excreted more sodium, but the SHRSP strain excreted more protein and a greater amount of sodium compared with either the WKY or the SP.WKYGla2k strain (0.19â±â0.02 vs. 0.12â±â0.01âg/24âh and 0.09â±â0.02âg/24âh, respectively). Glomerular filtration was not affected by diet or genotype, but renal plasma flow was decreased in the SP.WKYGla2k and SHRSP strains. The SHRSP strain had higher plasma aldosterone in association with greater adrenal CYP11B2 (aldosterone synthase) and 3ß hydroxysteroid dehydrogenase mRNA gene expression when compared to the WKY strain. Strikingly, introgression of the WKY chromosome 2 region into the SHRSP strain corrected the proteinuria and reduced sodium excretion, plasma aldosterone levels and 3ß hydroxysteroid dehydrogenase mRNA gene expression in response to the salt challenge when compared to the SHRSP strain. Glucocorticoid levels and markers of glucocorticoid synthesis were unaffected. CONCLUSION: Our findings suggest that introgression of the chromosome 2 congenic interval from the WKY into the SHRSP strain is associated with restored aldosterone regulation sufficient to reduce salt-sensitive hypertension and proteinuria.
Assuntos
Aldosterona/fisiologia , Hipertensão/induzido quimicamente , Hipertensão/genética , Locos de Características Quantitativas , Cloreto de Sódio na Dieta/efeitos adversos , Animais , Cromossomos/genética , Genótipo , Hipertensão/complicações , Rim/fisiopatologia , Masculino , Ratos , Ratos Endogâmicos SHR , Ratos Endogâmicos WKY , Acidente Vascular Cerebral/etiologiaRESUMO
The lineage of the Y chromosome accounts for up to 15 to 20 mm Hg in arterial pressure. Genes located on the Y chromosome from the spontaneously hypertensive rat (SHR) are associated with the renin-angiotensin system. Given the important role of the renin-angiotensin system in the renal regulation of fluid homeostasis and arterial pressure, we hypothesized that the origin of the Y chromosome influences arterial pressure via interaction between the intrarenal vasculature and the renin-angiotensin system. Sixteen-week-old normotensive rats (Wistar Kyoto [WKY]), spontaneously hypertensive stroke-prone rat (SHRSP), and 2 reciprocal Y consomic rat strains, 1 comprising the WKY autosomes and X chromosome with the Y chromosome from the hypertensive rat strain (WKY.SPGlaY) and vice versa (SP.WKYGlaY), were examined. SP.WKYGlaY had lower systolic blood pressure than SHRSP (195±5 versus 227±8 mm Hg; P<0.03), whereas WKY.SPGlaY had higher systolic blood pressure compared with WKY (157±3 versus 148±3 mm Hg; P<0.05), measured by radiotelemetry. Compared with WKY rats, SHRSP had higher plasma angiotensin(1-7) (Ang (1-7)):Ang II ratio (WKY: 0.13±0.01 versus SHRSP: 1.33±0.4; P<0.005), greater angiotensin II receptor type 2 and Mas receptor mRNA expression, and a blunted renal constrictor response to intrarenal Ang I and Ang(1-7) infusions. Introgression of the normotensive Y chromosome into the SHRSP background (SP.WKYGlaY) restored responses in the SHRSP to WKY levels, evidenced by a reduction in plasma Ang(1-7):Ang II ratio (SP.WKYGlaY: 0.24±0.02; P<0.01), angiotensin II receptor type 2, and Mas receptor mRNA expression and an increased vasoconstrictor response to intrarenal Ang I and Ang(1-7) infusion. This study demonstrates that the origin of the Y chromosome significantly impacts the renal vascular responsiveness and therefore may influence the long-term renal regulation of blood pressure.
Assuntos
Angiotensina I/farmacologia , Pressão Sanguínea/efeitos dos fármacos , Hipertensão/genética , Fragmentos de Peptídeos/farmacologia , Artéria Renal/fisiopatologia , Vasodilatação/efeitos dos fármacos , Cromossomo Y/genética , Animais , Modelos Animais de Doenças , Hipertensão/tratamento farmacológico , Hipertensão/fisiopatologia , Masculino , Ratos , Ratos Endogâmicos SHR , Ratos Endogâmicos WKY , Artéria Renal/efeitos dos fármacos , VasodilatadoresRESUMO
UNLABELLED: This single visit study examined whether endothelial function, in addition to cardiovascular (CV) risk factors and plasma microparticle content, was normalised in 15 patients with type 2 diabetes + acute coronary syndrome (ACS) (6 weeks-6 months post cardiac event) undergoing standard clinical care compared to 16 sex- and age-matched healthy controls. RESULTS: While total and low-density lipoprotein (LDL) cholesterol levels were well controlled in the patients with type 2 diabetes + ACS, residual CV risk profiles such as increased body mass index (BMI), systolic blood pressure, glucose levels and triglycerides and lower high-density lipoprotein (HDL) levels were still apparent. Endothelium-dependent responses to acetylcholine (ACh) were significantly lower in type 2 diabetes + ACS patients compared to controls. Correspondingly, the reactive hyperaemic index (RHI) was lower in the patient cohort. Endothelial microparticle (EMP) levels (CD31(+), CD41(-)) were 40% lower in the patient cohort. Simultaneous analysis of platelet microparticle (PMP) levels (CD41(+)) showed no difference between cohorts. CONCLUSIONS: Patients with type 2 diabetes suffering from recent ACS exhibit residual CV risk factors despite being on standard clinical care. In addition, these patients continue to present with endothelial dysfunction despite having lower levels of EMPs.
Assuntos
Síndrome Coronariana Aguda/fisiopatologia , Diabetes Mellitus Tipo 2/complicações , Endotélio Vascular/fisiopatologia , Síndrome Coronariana Aguda/etiologia , Síndrome Coronariana Aguda/metabolismo , Adulto , Idoso , Plaquetas/metabolismo , Pressão Sanguínea/fisiologia , LDL-Colesterol/sangue , Diabetes Mellitus Tipo 2/metabolismo , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Fatores de RiscoRESUMO
BACKGROUND: Sex differences in the expression of the angiotensin (Ang) II receptors and angiotensin-converting enzyme 2 (ACE2) have been hypothesized to be a potential mechanism contributing to sex-specific differences in arterial pressure. Currently, sex differences in the expression of the angiotensin receptors and ACE2 remain undefined. OBJECTIVES: The aim of this study was to define the postnatal ontogeny of mRNA expression, from birth to adulthood, of the Ang II and Ang-(1-7) receptors and ACE2 in male and female rats. METHODS: Kidney and heart tissue was collected from male and female Sprague Dawley rats and snap-frozen at postnatal days (PNDs) 1, 30, 42, 70, and 110 (adult), and real-time polymerase chain reaction was performed to determine relative expression of the Ang II and Ang-(1-7) receptors (AT(1a)R, AT(1b)R, AT(2)R, and MasR) and ACE2. RESULTS: All these components of the renin-angiotensin system (RAS) were detected in the kidney and left ventricle, although expression levels differed significantly between the sexes and across organs. Gene expression of most components of the RAS was high at birth and decreased with age in both sexes, except for ACE2 expression, which increased in the left ventricle with age (P(Age) < 0.001). Low levels of AT(2)R were observed in the ventricles in both sexes as adults. Most notably, AT(2)R expression was greatest in female kidneys and lowest in male kidneys compared with the left ventricle (P(Age*Sex) < 0.05). Interestingly, MasR expression in the female kidney was similar to the level of AT(2)R expression. Left ventricular MasR expression was greater than AT(2)R expression in both sexes but was not different between the sexes. The highest level of ACE2 expression was observed in adult female kidneys (P(AS) < 0.05). CONCLUSIONS: The enhanced mRNA expression of the vasodilatory arm of the renal RAS (ACE2, AT(2)R) in females observed in the present study may contribute to sex differences in the regulation of arterial pressure and the incidence of cardiovascular disease in women.
Assuntos
Expressão Gênica , Rim/metabolismo , Peptidil Dipeptidase A/metabolismo , RNA Mensageiro/metabolismo , Receptor Tipo 1 de Angiotensina/metabolismo , Receptores de Angiotensina/metabolismo , Angiotensina I/genética , Angiotensina I/metabolismo , Enzima de Conversão de Angiotensina 2 , Animais , Feminino , Masculino , Fragmentos de Peptídeos/genética , Fragmentos de Peptídeos/metabolismo , Peptidil Dipeptidase A/genética , Ratos , Ratos Sprague-Dawley , Receptor Tipo 1 de Angiotensina/genética , Receptores de Angiotensina/genética , Fatores SexuaisRESUMO
Sexual dimorphism in arterial pressure regulation has been observed in humans and animal models. The mechanisms underlying this gender difference are not fully known. Previous studies in rats have shown that females excrete more salt than males at a similar arterial pressure. The renin-angiotensin system is a powerful regulator of arterial pressure and body fluid volume. This study examined the role of the angiotensin type 2 receptor (AT2R) in pressure-natriuresis in male and female rats because AT2R expression has been reported to be enhanced in females. Renal function was examined at renal perfusion pressures of 120, 100, and 80 mm Hg in vehicle-treated and AT2R antagonist-treated (PD123319; 1 mg/kg/h) groups. The pressure-natriuresis relationship was gender-dependent such that it was shifted upward in female vs male rats (P < 0.001). AT2R blockade modulated the pressure-natriuresis relationship, shifting the curve downward in male (P < 0.01) and female (P < 0.01) rats to a similar extent. In females, AT2R blockade also reduced the lower end of the autoregulatory range of renal blood flow (P < 0.05) and glomerular filtration rate (P < 0.01). Subsequently, the renal blood flow response to graded angiotensin II infusion was also measured with and without AT2R blockade. We found that AT2R blockade enhanced the renal vasoconstrictor response to angiotensin II in females but not in males (P < 0.05). In conclusion, the AT2R modulates pressure-natriuresis, allowing the same level of sodium to be excreted at a lower pressure in both genders. However, a gender-specific role for the AT2R in renal autoregulation was evident in females, which may be a direct vascular AT2R effect.
Assuntos
Homeostase/fisiologia , Rim/fisiologia , Natriurese/fisiologia , Receptor Tipo 2 de Angiotensina/fisiologia , Análise de Variância , Angiotensina II/farmacologia , Bloqueadores do Receptor Tipo 2 de Angiotensina II/farmacologia , Animais , Peso Corporal/fisiologia , Feminino , Homeostase/efeitos dos fármacos , Humanos , Imidazóis/farmacologia , Rim/anatomia & histologia , Masculino , Natriurese/efeitos dos fármacos , Tamanho do Órgão , Pressão , Piridinas/farmacologia , Ratos , Ratos Sprague-Dawley , Circulação Renal/fisiologia , Fatores Sexuais , Vasoconstritores/farmacologiaRESUMO
The renin-angiotensin system is a far more complex enzymatic cascade than realized previously. Mounting evidence suggests sex-specific differences in the regulation of the renin-angiotensin system and arterial pressure. We examined the hemodynamic responses, angiotensin II receptor subtypes, and angiotensin-converting enzyme 2 gene expression levels after graded doses of angiotensin II in males and females. Mean arterial pressure was measured via telemetry in male and female rats in response to a 2-week infusion of vehicle, low-dose (50 ng/kg per minute SC) or high-dose (400 ng/kg per minute SC) angiotensin II. The effect of concurrent infusion of the angiotensin II type 2 receptor (AT(2)R) blocker (PD123319) was also examined. The arterial pressure response to high-dose angiotensin II was attenuated in females compared with males (24+/-8 mm Hg versus 42+/-5 mm Hg; P for the interaction between sex and treatment <0.002). Remarkably, low-dose angiotensin II decreased arterial pressure (11+/-4 mm Hg; P for the interaction between sex and treatment <0.02) at a dose that did not have an effect in males. This decrease in arterial pressure in females was abolished by AT(2)R blockade. Renal AT(2)R, angiotensin-converting enzyme 2, and left ventricular AT(2)R mRNA gene expressions were markedly greater in females than in males with a renal angiotensin II type 1a receptor:AT(2)R ratio of approximately 1 in females. Angiotensin II infusion did not affect renal AT(2)R mRNA expression but resulted in significantly less left ventricular mRNA expression. Renal angiotensin-converting enzyme 2 mRNA expression levels were greater in females than in males treated with high-dose angiotensin II (approximately 2.5 fold; P for the interaction between sex and treatment <0.05). In females, enhancement of the vasodilatory arm of the renin-angiotensin system, in particular, AT(2)R and angiotensin-converting enzyme 2 mRNA expression, may contribute to the sex-specific differences in response to renin-angiotensin system activation.
Assuntos
Pressão Sanguínea/fisiologia , Regulação da Expressão Gênica , Ventrículos do Coração/metabolismo , Hipertensão/genética , Rim/metabolismo , RNA Mensageiro/genética , Receptor Tipo 2 de Angiotensina/genética , Angiotensina II/administração & dosagem , Angiotensina II/toxicidade , Animais , Pressão Sanguínea/efeitos dos fármacos , Doença Crônica , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Feminino , Hipertensão/induzido quimicamente , Hipertensão/fisiopatologia , Masculino , Ratos , Ratos Sprague-Dawley , Receptor Tipo 2 de Angiotensina/biossíntese , Vasodilatação/efeitos dos fármacos , Vasodilatação/fisiologiaAssuntos
Doenças Cardiovasculares , Avaliação da Deficiência , Predisposição Genética para Doença , Hemodinâmica/fisiologia , Cromossomo X , Cromossomo Y , Fatores Etários , Animais , Doenças Cardiovasculares/epidemiologia , Doenças Cardiovasculares/genética , Doenças Cardiovasculares/fisiopatologia , Causas de Morte , Bandeamento Cromossômico , Humanos , Masculino , Fatores de Risco , Taxa de SobrevidaRESUMO
We investigated the roles of the renin-angiotensin system and the significance of interactions between angiotensin II and nitric oxide, in responses of regional kidney perfusion to electrical renal nerve stimulation (RNS) in pentobarbital sodium-anesthetized rabbits. Under control conditions, RNS (0.5-8 Hz) reduced total renal blood flow (RBF; -89 +/- 3% at 8 Hz) and cortical perfusion (CBF; -90 +/- 2% at 8 Hz) more than medullary perfusion (MBF; -55 +/- 5% at 8 Hz). Angiotensin II type 1 (AT(1))-receptor antagonism (candesartan) blunted RNS-induced reductions in RBF (P = 0.03), CBF (P = 0.007), and MBF (P = 0.04), particularly at 4 and 8 Hz. Nitric oxide synthase inhibition with N(G)-nitro-L-arginine (L-NNA) enhanced RBF (P = 0.003), CBF (P = 0.001), and MBF (P = 0.03) responses to RNS, particularly at frequencies of 2 Hz and less. After candesartan pretreatment, L-NNA significantly enhanced RNS-induced reductions in RBF (P = 0.04) and CBF (P = 0.007) but not MBF (P = 0.66). Renal arterial infusion of angiotensin II (5 ng.kg(-1).min(-1)) selectively enhanced responses of MBF to RNS in L-NNA-pretreated but not in vehicle-pretreated rabbits. In contrast, greater doses of angiotensin II (5-15 ng.kg(-1).min(-1)) blunted responses of MBF to RNS in rabbits with intact nitric oxide synthase. These results suggest that endogenous angiotensin II enhances, whereas nitric oxide blunts, neurally mediated vasoconstriction in the renal cortical and medullary circulations. In the renal medulla, but not the cortex, angiotensin II also appears to be able to blunt neurally mediated vasoconstriction.