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1.
Proc Natl Acad Sci U S A ; 117(3): 1753-1761, 2020 01 21.
Artículo en Inglés | MEDLINE | ID: mdl-31896584

RESUMEN

Carbon dioxide (CO2), the major product of metabolism, has a strong impact on cerebral blood vessels, a phenomenon known as cerebrovascular reactivity. Several vascular risk factors such as hypertension or diabetes dampen this response, making cerebrovascular reactivity a useful diagnostic marker for incipient vascular pathology, but its functional relevance, if any, is still unclear. Here, we found that GPR4, an endothelial H+ receptor, and endothelial Gαq/11 proteins mediate the CO2/H+ effect on cerebrovascular reactivity in mice. CO2/H+ leads to constriction of vessels in the brainstem area that controls respiration. The consequential washout of CO2, if cerebrovascular reactivity is impaired, reduces respiration. In contrast, CO2 dilates vessels in other brain areas such as the amygdala. Hence, an impaired cerebrovascular reactivity amplifies the CO2 effect on anxiety. Even at atmospheric CO2 concentrations, impaired cerebrovascular reactivity caused longer apneic episodes and more anxiety, indicating that cerebrovascular reactivity is essential for normal brain function. The site-specific reactivity of vessels to CO2 is reflected by regional differences in their gene expression and the release of vasoactive factors from endothelial cells. Our data suggest the central nervous system (CNS) endothelium as a target to treat respiratory and affective disorders associated with vascular diseases.


Asunto(s)
Ansiedad/metabolismo , Sistema Cardiovascular/metabolismo , Endotelio/metabolismo , Trastornos Respiratorios/metabolismo , Amígdala del Cerebelo , Animales , Arteriolas/patología , Encéfalo/fisiología , Tronco Encefálico/metabolismo , Dióxido de Carbono/metabolismo , Sistema Nervioso Central/metabolismo , Modelos Animales de Enfermedad , Endotelio/patología , Subunidades alfa de la Proteína de Unión al GTP Gq-G11/genética , Subunidades alfa de la Proteína de Unión al GTP Gq-G11/metabolismo , Expresión Génica , Humanos , Hipercapnia/metabolismo , Ratones , Ratones Noqueados , Ratones Transgénicos , Receptores Acoplados a Proteínas G/genética , Receptores Acoplados a Proteínas G/metabolismo , Respiración , Factores de Riesgo , Transducción de Señal
2.
Pflugers Arch ; 474(9): 993-1002, 2022 09.
Artículo en Inglés | MEDLINE | ID: mdl-35648220

RESUMEN

Investigating atherosclerosis and endothelial dysfunction has mainly become established in genetically modified ApoE-/- or LDL-R-/- mice transgenic models. A new AAV-PCSK9DYDY mouse model with no genetic modification has now been reported as an alternative atherosclerosis model. Here, we aimed to employ this AAV-PCSK9DY mouse model to quantify the mechanical stiffness of the endothelial surface, an accepted hallmark for endothelial dysfunction and forerunner for atherosclerosis. Ten-week-old male C57BL/6 N mice were injected with AAV-PCSK9DY (0.5, 1 or 5 × 1011 VG) or saline as controls and fed with Western diet (1.25% cholesterol) for 3 months. Total cholesterol (TC) and triglycerides (TG) were measured after 6 and 12 weeks. Aortic sections were used for atomic force microscopy (AFM) measurements or histological analysis using Oil-Red-O staining. Mechanical properties of in situ endothelial cells derived from ex vivo aorta preparations were quantified using AFM-based nanoindentation. Compared to controls, an increase in plasma TC and TG and extent of atherosclerosis was demonstrated in all groups of mice in a viral load-dependent manner. Cortical stiffness of controls was 1.305 pN/nm and increased (10%) in response to viral load (≥ 0.5 × 1011 VG) and positively correlated with the aortic plaque content and plasma TC and TG. For the first time, we show changes in the mechanical properties of the endothelial surface and thus the development of endothelial dysfunction in the AAV-PCSK9DY mouse model. Our results demonstrate that this model is highly suitable and represents a good alternative to the commonly used transgenic mouse models for studying atherosclerosis and other vascular pathologies.


Asunto(s)
Aterosclerosis , Proproteína Convertasa 9 , Animales , Aterosclerosis/patología , Colesterol , Modelos Animales de Enfermedad , Células Endoteliales/patología , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Microscopía de Fuerza Atómica , Proproteína Convertasa 9/genética , Triglicéridos
3.
Pharmacol Res ; 170: 105724, 2021 08.
Artículo en Inglés | MEDLINE | ID: mdl-34116209

RESUMEN

Telmisartan prevents diet-induced obesity (DIO) in rodents. Given that the precise underlying mechanism is not known, we examined whether a gut-related mechanism might be involved. Sprague-Dawley rats received cafeteria diet (CD) for 3 months to develop DIO and were administered either telmisartan (8 mg/kgbw) or vehicle. In addition, pair-fed (PF) rats received CD adjusted to TEL and control rats (CON) only received chow. Stool samples were analysed by 16 S rRNA gene amplicon sequencing. CD-fed rats became obese while TEL, PF and CON rats remained lean. Alpha diversity analyses indicated that bacterial diversity was similar before the study but changed over time. Beta diversity revealed a time-, CD- and telmisartan-dependent effect. The Firmicutes/Bacteroidetes ratio and the abundance of Blautia, Allobaculum and Parasutterella were higher in DIO and PF than in CON, but not in TEL. Enterotype (ET)-like clustering analyses, Kleinberg's hub network scoring and random forest analyses also indicated that telmisartan induced a specific signature of gut microbiota. In response to stool transfer from telmisartan-pre-treated donor to high-fat fed acceptor mice, body weight gain was slightly attenuated. We attribute the anti-obesity action of telmisartan treatment to diet-independent alterations in gut microbiota as the microbiota from telmisartan-treated, CD-fed rats clearly differed from those of DIO and PF rats. ET-like clustering network, random forest classification and the higher stability in bacterial co-occurrence network analyses indicate that there is more than one indicator species for telmisartan's specific signature, which is further strengthened by the fact that we cannot identify a single indicator species.


Asunto(s)
Bloqueadores del Receptor Tipo 1 de Angiotensina II/farmacología , Fármacos Antiobesidad/farmacología , Bacterias/efectos de los fármacos , Microbioma Gastrointestinal/efectos de los fármacos , Obesidad/tratamiento farmacológico , Telmisartán/farmacología , Aumento de Peso/efectos de los fármacos , Animales , Bacterias/crecimiento & desarrollo , Dieta/efectos adversos , Modelos Animales de Enfermedad , Disbiosis , Trasplante de Microbiota Fecal , Heces/microbiología , Ratones , Obesidad/etiología , Obesidad/microbiología , Obesidad/fisiopatología , Ratas , Ratas Sprague-Dawley
4.
Pflugers Arch ; 470(6): 867-881, 2018 06.
Artículo en Inglés | MEDLINE | ID: mdl-29430615

RESUMEN

Considering that obesity is one of the leading risks for death worldwide, it should be noted that a brain-related mechanism is involved in AngII-induced and AT1-receptor-dependent weight loss. It is moreover established that activation of the Ang(1-7)/ACE2/Mas axis reduces weight, but it remains unclear whether this Ang(1-7) effect is also mediated via a brain-related mechanism. Additionally to Sprague Dawley (SD) rats, we used TGR(ASrAOGEN) selectively lacking brain angiotensinogen, the precursor to AngII, as we speculated that effects are more pronounced in a model with low brain RAS activity. Rats were fed with high-calorie cafeteria diet. We investigated weight regulation, food behavior, and energy balance in response to chronic icv.-infusions of AngII (200 ng•h-1), or Ang(1-7) (200/600 ng•h-1) or artificial cerebrospinal fluid. High- but not low-dose Ang(1-7) slightly decreased weight gain and energy intake in SD rats. AngII showed an anti-obese efficacy in SD rats by decreasing energy intake and increasing energy expenditure and also improved glucose control. TGR(ASrAOGEN) were protected from developing obesity. However, Ang(1-7) did not reveal any effects in TGR(ASrAOGEN) and those of AngII were minor compared to SD rats. Our results emphasize that brain AngII is a key contributor for regulating energy homeostasis and weight in obesity by serving as a negative brain-related feedback signal to alleviate weight gain. Brain-related anti-obese potency of Ang(1-7) is lower than AngII but must be further investigated by using other transgenic models as TGR(ASrAOGEN) proved to be less valuable for answering this question.


Asunto(s)
Angiotensina I/uso terapéutico , Fármacos Antiobesidad/uso terapéutico , Obesidad/prevención & control , Fragmentos de Péptidos/uso terapéutico , Angiotensina I/administración & dosificación , Animales , Fármacos Antiobesidad/administración & dosificación , Dieta Alta en Grasa/efectos adversos , Infusiones Intraventriculares , Masculino , Obesidad/tratamiento farmacológico , Obesidad/etiología , Fragmentos de Péptidos/administración & dosificación , Ratas , Ratas Sprague-Dawley
5.
Pflugers Arch ; 470(11): 1673-1689, 2018 11.
Artículo en Inglés | MEDLINE | ID: mdl-29978352

RESUMEN

Obesity is a global health problem and treatment options are still insufficient. When chronically treated with the angiotensin II receptor blocker telmisartan (TEL), rodents do not develop diet-induced obesity (DIO). However, the underlying mechanism for this is still unclear. Here we investigated whether TEL prevents leptin resistance by enhancing leptin uptake across the blood-brain barrier (BBB). To address this question, we fed C57BL/6 mice a high-fat diet (HFD) and treated them daily with TEL by oral gavage. In addition to broadly characterizing the metabolism of leptin, we determined leptin uptake into the brain by measuring BBB transport of radioactively labeled leptin after long-term and short-term TEL treatment. Additionally, we assessed BBB integrity in response to angiotensin II in vitro and in vivo. We found that HFD markedly increased body weight, energy intake, and leptin concentration but that this effect was abolished under TEL treatment. Furthermore, glucose control and, most importantly, leptin uptake across the BBB were impaired in mice on HFD, but, again, both were preserved under TEL treatment. BBB integrity was not impaired due to angiotensin II or blocking of angiotensin II receptors. However, TEL did not exhibit an acute effect on leptin uptake across the BBB. Our results confirm that TEL prevents DIO and show that TEL preserves leptin transport and thereby prevents leptin resistance. We conclude that the preservation of leptin sensitivity is, however, more a consequence than the cause of TEL preventing body weight gain.


Asunto(s)
Bloqueadores del Receptor Tipo 1 de Angiotensina II/uso terapéutico , Fármacos Antiobesidad/uso terapéutico , Barrera Hematoencefálica/metabolismo , Leptina/metabolismo , Obesidad/tratamiento farmacológico , Telmisartán/uso terapéutico , Bloqueadores del Receptor Tipo 1 de Angiotensina II/farmacología , Animales , Fármacos Antiobesidad/farmacología , Barrera Hematoencefálica/efectos de los fármacos , Peso Corporal , Línea Celular , Dieta Alta en Grasa/efectos adversos , Metabolismo Energético , Humanos , Masculino , Ratones , Ratones Endogámicos C57BL , Obesidad/etiología , Obesidad/metabolismo , Telmisartán/farmacología
6.
Pharmacol Res ; 125(Pt A): 72-90, 2017 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-28687340

RESUMEN

Cardiovascular diseases (CVD) are among the main causes of death globally and in this context hypertension represents one of the key risk factors for developing a CVD. It is well established that the peripheral renin-angiotensin system (RAS) plays an important role in regulating blood pressure (BP). All components of the classic RAS can also be found in the brain but, in contrast to the peripheral RAS, how the endogenous RAS is involved in modulating cardiovascular effects in the brain is not fully understood yet. It is a complex system that may work differently in diverse areas of the brain and is linked to the peripheral system by the circumventricular organs (CVO), which do not have a blood brain barrier (BBB). In this review, we focus on the brain angiotensin peptides, their interactions with each other, and the consequences in the central nervous system (CNS) concerning cardiovascular control. Additionally, we present potential drug targets in the brain RAS for the treatment of hypertension.


Asunto(s)
Angiotensinas/metabolismo , Encéfalo/fisiopatología , Enfermedades Cardiovasculares/patología , Sistema Renina-Angiotensina/fisiología , Animales , Presión Sanguínea/fisiología , Encéfalo/metabolismo , Enfermedades Cardiovasculares/metabolismo , Humanos
7.
Front Endocrinol (Lausanne) ; 15: 1338458, 2024.
Artículo en Inglés | MEDLINE | ID: mdl-38469142

RESUMEN

Introduction: The development of cognitive dysfunction is not necessarily associated with diet-induced obesity. We hypothesized that cognitive dysfunction might require additional vascular damage, for example, in atherosclerotic mice. Methods: We induced atherosclerosis in male C57BL/6N mice by injecting AAV-PCSK9DY (2x1011 VG) and feeding them a cholesterol-rich Western diet. After 3 months, mice were examined for cognition using Barnes maze procedure and for cerebral blood flow. Cerebral vascular morphology was examined by immunehistology. Results: In AAV-PCSK9DY-treated mice, plaque burden, plasma cholesterol, and triglycerides are elevated. RNAseq analyses followed by KEGG annotation show increased expression of genes linked to inflammatory processes in the aortas of these mice. In AAV-PCSK9DY-treated mice learning was delayed and long-term memory impaired. Blood flow was reduced in the cingulate cortex (-17%), caudate putamen (-15%), and hippocampus (-10%). Immunohistological studies also show an increased incidence of string vessels and pericytes (CD31/Col IV staining) in the hippocampus accompanied by patchy blood-brain barrier leaks (IgG staining) and increased macrophage infiltrations (CD68 staining). Discussion: We conclude that the hyperlipidemic PCSK9DY mouse model can serve as an appropriate approach to induce microvascular dysfunction that leads to reduced blood flow in the hippocampus, which could explain the cognitive dysfunction in these mice.


Asunto(s)
Aterosclerosis , Hiperlipidemias , Masculino , Ratones , Animales , Proproteína Convertasa 9/genética , Incidencia , Ratones Endogámicos C57BL , Hiperlipidemias/patología , Aterosclerosis/metabolismo , Colesterol , Circulación Cerebrovascular/fisiología
8.
Autoimmun Rev ; 22(2): 103236, 2023 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-36436750

RESUMEN

Approximately 5% of the world-wide population is affected by autoimmune diseases. Overall, autoimmune diseases are still difficult to treat, impose a high burden on patients, and have a significant economic impact. Like other complex diseases, e.g., cancer, autoimmune diseases develop over several years. Decisive steps in the development of autoimmune diseases are (i) the development of autoantigen-specific lymphocytes and (often) autoantibodies and (ii) potentially clinical disease manifestation at a later stage. However, not all healthy individuals with autoantibodies develop disease manifestations. Identifying autoantibody-positive healthy individuals and monitoring and inhibiting their switch to inflammatory autoimmune disease conditions are currently in their infancy. The switch from harmless to inflammatory autoantigen-specific T and B-cell and autoantibody responses seems to be the hallmark for the decisive factor in inflammatory autoimmune disease conditions. Accordingly, biomarkers allowing us to predict this progression would have a significant impact. Several factors, such as genetics and the environment, especially diet, smoking, exposure to pollutants, infections, stress, and shift work, might influence the progression from harmless to inflammatory autoimmune conditions. To inspire research directed at defining and ultimately targeting autoimmune predisease, here, we review published evidence underlying the progression from health to autoimmune predisease and ultimately to clinically manifest inflammatory autoimmune disease, addressing the following 3 questions: (i) what is the current status, (ii) what is missing, (iii) and what are the future perspectives for defining and modulating autoimmune predisease.


Asunto(s)
Enfermedades Autoinmunes , Autoinmunidad , Humanos , Enfermedades Autoinmunes/etiología , Autoanticuerpos , Autoantígenos , Linfocitos
9.
J Vasc Res ; 49(3): 260-6, 2012.
Artículo en Inglés | MEDLINE | ID: mdl-22456468

RESUMEN

BACKGROUND/AIMS: Reduction of capillary network density occurs early in the development of metabolic syndrome and may be relevant for the precipitation of diabetes. Agonists of the peroxisome proliferator-activated receptor (PPAR)-γ transcription factor are vasculoprotective, but their capacity for structural preservation of the microcirculation is unclear. METHODS: Male Wistar rats were rendered diabetic by streptozotocin and treated with pioglitazone in chow for up to 12 weeks. Capillary density was determined in heart and skeletal muscle after platelet endothelial cell adhesion molecule-1 (PECAM-1) immunostaining. Hallmarks of apoptosis and angiogenesis were determined. RESULTS: Capillary density deteriorated progressively in the presence of hyperglycemia (from 971/mm2 to 475/mm2 in quadriceps muscle during 13 weeks). Pioglitazone did not influence plasma glucose, left ventricular weight, or body weight but nearly doubled absolute and relative capillary densities compared to untreated controls (1.2 vs. 0.6 capillaries/myocyte in heart and 1.5 vs. 0.9 capillaries/myocyte in quadriceps muscle) after 13 weeks of diabetes. No antiapoptotic or angiogenic influence of pioglitazone was detected while a reduced expression of hypoxia-inducible factor-3α and PPAR coactivator-1α (PGC-1α) mRNA as well as vascular endothelial growth factor (VEGF) protein possibly occurred as a consequence of improved vascularization. CONCLUSION: Pioglitazone preserves microvascular structure in diabetes independently of improvements in glycemic control and by a mechanism unrelated to VEGF-mediated angiogenesis.


Asunto(s)
Glucemia/análisis , Capilares/efectos de los fármacos , Diabetes Mellitus Experimental/tratamiento farmacológico , Hipoglucemiantes/farmacología , Tiazolidinedionas/farmacología , Factor A de Crecimiento Endotelial Vascular/fisiología , Animales , Apoptosis/efectos de los fármacos , Capilares/fisiopatología , Diabetes Mellitus Experimental/sangre , Masculino , PPAR gamma/fisiología , Pioglitazona , Ratas , Ratas Wistar , Estreptozocina , Tiazolidinedionas/uso terapéutico , Factor A de Crecimiento Endotelial Vascular/análisis
10.
Front Pharmacol ; 13: 815353, 2022.
Artículo en Inglés | MEDLINE | ID: mdl-35431918

RESUMEN

The angiotensin II (type 1) (AT1) receptor blocker telmisartan (TEL) is beneficial for the treatment of individuals suffering from metabolic syndrome. As we have shown that TEL has an impact on gut microbiota, we investigated here whether TEL influences gut barrier function. C57BL/6N mice were fed with chow or high-fat diet (HFD) and treated with vehicle or TEL (8 mg/kg/day). Mucus thickness was determined by immunohistochemistry. Periodic Acid-Schiff staining allowed the number of goblet cells to be counted. Using western blots, qPCR, and immunohistochemistry, factors related to mucus biosynthesis (Muc2, St6galnac), proliferation (Ki-67), or necroptosis (Rip3) were measured. The influence on cell viability was determined in vitro by using losartan, as the water solubility of TEL was too low for in vitro experiments. Upon HFD, mice developed obesity as well as leptin and insulin resistance, which were prevented by TEL. Mucus thickness upon HFD-feeding was diminished. Independent of feeding, TEL additionally reduced mucus thickness. Numbers of goblet cells were not affected by HFD-feeding and TEL. St6galnac expression was increased by TEL. Rip3 was increased in TEL-treated and HFD-fed mice, while Ki-67 decreased. Cell viability was diminished by using >1 mM losartan. The anti-obese effect of TEL was associated with a decrease in mucus thickness, which was likely not related to a lower expression of Muc2 and goblet cells. A decrease in Ki-67 and increase in Rip3 indicates lower cell proliferation and increased necroptosis upon TEL. However, direct cell toxic effects are ruled out, as in vivo concentrations are lower than 1 mM.

11.
J Cereb Blood Flow Metab ; 41(9): 2356-2369, 2021 09.
Artículo en Inglés | MEDLINE | ID: mdl-33730932

RESUMEN

Angiotensin II receptor blockers (telmisartan) prevent rodents from diet-induced obesity and improve their metabolic status. Hyperglycemia and obesity are associated with reduced cerebral blood flow and neurovascular uncoupling which may lead to behavioral deficits. We wanted to know whether a treatment with telmisartan prevents these changes in obesity.We put young mice on high-fat diet and simultaneously treated them with telmisartan. At the end of treatment, we performed laser speckle imaging and magnetic resonance imaging to assess the effect on neurovascular coupling and cerebral blood flow. Different behavioral tests were used to investigate cognitive function.Mice developed diet-induced obesity and after 16, not 8 weeks of high-fat diet, however, the response to whisker pad stimulation was about 30% lower in obese compared to lean mice. Simultaneous telmisartan treatment increased the response again by 10% compared to obese mice. Moreover, telmisartan treatment normalized high-fat diet-induced reduction of cerebral blood flow and prevented a diet-induced anxiety-like behavior. In addition to that, telmisartan affects cellular senescence and string vessel formation in obesity.We conclude, that telmisartan protects against neurovascular unit impairments in a diet-induced obesity setting and may play a role in preventing obesity related cognitive deficits in Alzheimer's disease.


Asunto(s)
Bloqueadores del Receptor Tipo 1 de Angiotensina II/uso terapéutico , Ansiedad/tratamiento farmacológico , Dieta Alta en Grasa/efectos adversos , Obesidad/fisiopatología , Telmisartán/uso terapéutico , Bloqueadores del Receptor Tipo 1 de Angiotensina II/farmacología , Animales , Modelos Animales de Enfermedad , Masculino , Ratones , Telmisartán/farmacología
12.
Ann Nutr Metab ; 56(2): 127-42, 2010.
Artículo en Inglés | MEDLINE | ID: mdl-20134158

RESUMEN

BACKGROUND/AIMS: The metabolic syndrome (MS) has become an epidemiological problem in Western countries. We developed a diet-induced obese rat model that mimics all the symptoms of MS in humans, but whose insulin resistance, hyperphagia and hyperleptinemia are caused by nutrition rather than genetic modifications. METHODS: Spontaneously hypertensive rats (SHR) were allowed for 12 weeks to choose between a cafeteria diet (CD, 20.3 kJ/g) and standard rat chow (11.7 kJ/g). Controls received rat chow. RESULTS: Body weight (BW) exceeded control levels when SHR were fed with CD. The increase in BW was attributed to enhanced energy intake. The abundance of abdominal fat as well as the plasma levels of leptin and triglycerides increased concomitant with glucose, insulin and C-peptide. This prediabetic condition was further confirmed by a markedly increased insulin response following glucose challenge and by impaired glucose utilization after insulin tolerance tests. CONCLUSION: Increases in food intake and BW despite hyperleptinemia indicate leptin resistance following CD feeding. CD-fed SHR feature leptin and insulin resistance, hypertension and obesity, thus mimicking the situation of MS patients. As such, our model is more suitable than the genetically modified rat models used to study human MS.


Asunto(s)
Hiperfagia/complicaciones , Síndrome Metabólico/etiología , Obesidad/etiología , Grasa Abdominal , Animales , Biomarcadores/sangre , Glucemia , Presión Sanguínea , Peso Corporal , Péptido C/sangre , Dieta/efectos adversos , Dieta/métodos , Modelos Animales de Enfermedad , Ingestión de Energía , Frecuencia Cardíaca , Hiperfagia/sangre , Insulina/sangre , Resistencia a la Insulina , Leptina/sangre , Masculino , Síndrome Metabólico/sangre , Obesidad/sangre , Ratas , Ratas Endogámicas SHR , Ratas Sprague-Dawley , Triglicéridos/sangre
13.
J Endocrinol ; 244(1): 95-110, 2020 01 01.
Artículo en Inglés | MEDLINE | ID: mdl-31585441

RESUMEN

The AT1 receptor blocker telmisartan (TEL) prevents diet-induced obesity. Hypothalamic lipid metabolism is functionally important for energy homeostasis, as a surplus of lipids induces an inflammatory response in the hypothalamus, thus promoting the development of central leptin resistance. However, it is unclear as to whether TEL treatment affects the lipid status in the hypothalamus. C57BL/6N mice were fed with chow (CONchow) or high-fat diet (CONHFD). HFD-fed mice were gavaged with TEL (8 mg/kg/day, 12 weeks, TELHFD). Mice were phenotyped regarding weight gain, energy homeostasis, and glucose control. Hypothalamic lipid droplets were analyzed by fluorescence microscopy. Lipidomics were assessed by performing liquid chromatography-mass spectrometry in plasma and hypothalami. Adipokines were investigated using immunosorbent assays. Glial fibrillary acidic protein (GFAP) was determined by Western blotting and immunohistochemical imaging. We found that body weight, energy homeostasis, and glucose control of TEL-treated mice remained normal while CONHFD became obese. Hypothalamic ceramide and triglyceride levels as well as alkyne oleate distribution were normalized in TELHFD. The lipid droplet signal in the tanycyte layer was higher in CONHFD than in CONchow and returned to normal under TELHFD conditions. High hypothalamic levels of GFAP protein indicate astrogliosis of CONHFD mice while normalized GFAP, TNFα, and IL1α levels of TELHFD mice suggest that TEL prevents hypothalamic inflammation. In conclusion, TEL has anti-obese efficacy and prevented lipid accumulation and lipotoxicity, which is accompanied by an anti-inflammatory effect in the murine hypothalamus. Our findings support the notion that a brain-related mechanism is involved in TEL-induced weight loss.


Asunto(s)
Bloqueadores del Receptor Tipo 1 de Angiotensina II/administración & dosificación , Gotas Lipídicas/efectos de los fármacos , Obesidad/prevención & control , Telmisartán/administración & dosificación , Aumento de Peso/efectos de los fármacos , Alimentación Animal , Animales , Dieta Alta en Grasa/efectos adversos , Hipotálamo/metabolismo , Leptina/metabolismo , Metabolismo de los Lípidos/efectos de los fármacos , Ratones , Ratones Endogámicos C57BL , Obesidad/etiología
14.
Naunyn Schmiedebergs Arch Pharmacol ; 392(7): 865-877, 2019 07.
Artículo en Inglés | MEDLINE | ID: mdl-30868173

RESUMEN

We recently showed that the antiobese efficacy of the AT1 receptor blocker telmisartan (TEL) is at least partially related to an Ang(1-7)-dependent mechanism. Ang(1-7) acts via Mas, thus raising the question of whether Mas-deficient (Mas-ko) mice are likewise predisposed to develop diet-induced obesity and, further, whether this can be prevented by TEL treatment. Mas-ko mice and FVB/N wild-type (wt) animals were treated with TEL (8 mg/kg/day) or vehicle while they were fed with high-fat diet (HFD) or chow. Mice were phenotyped regarding body weight, fat mass, insulin sensitivity, and leptin sensitivity. In response to HFD feeding, gain in body weight and impairment of leptin sensitivity were similar between wt and Mas-ko mice. TEL reduced body weight in both strains but effects were stronger in Mas-ko mice. TEL diminished fat mass and restored leptin sensitivity only in Mas-ko mice. Blood glucose was higher in wt than Mas-ko mice fed with HFD while not differing when they were fed with chow. Insulin challenge confirmed that wt mice became insulin resistant when fed with HFD while HFD feeding did not impair insulin sensitivity in Mas-ko mice. TEL had no further effect. Our findings on the influence of TEL on growth and metabolism in Mas-ko mice conflict with our previous findings in rats. We assume that the FVB/N background of the mice may partly explain these inconsistent data. Moreover, it also seems feasible that the MrgD receptor compensates for Mas deficiency.


Asunto(s)
Bloqueadores del Receptor Tipo 1 de Angiotensina II/farmacología , Fármacos Antiobesidad/farmacología , Obesidad/metabolismo , Proteínas Proto-Oncogénicas/deficiencia , Receptor de Angiotensina Tipo 1/metabolismo , Receptores Acoplados a Proteínas G/deficiencia , Telmisartán/farmacología , Animales , Peso Corporal/efectos de los fármacos , Peso Corporal/genética , Dieta Alta en Grasa , Ratones Noqueados , Obesidad/tratamiento farmacológico , Obesidad/etiología , Proto-Oncogenes Mas , Proteínas Proto-Oncogénicas/genética , Receptores Acoplados a Proteínas G/genética
15.
Naunyn Schmiedebergs Arch Pharmacol ; 392(2): 229-241, 2019 02.
Artículo en Inglés | MEDLINE | ID: mdl-30368548

RESUMEN

Infections are a major problem in patients with burn diseases. Mortality is high despite antibiotic therapy as studies are controversial concerning drug underdosing. The aims of this prospective, observational study were to monitor plasma concentrations of piperacillin during standard piperacillin/tazobactam treatment in 20 burn patients and 16 controls from the intensive care unit (ICU) and to optimize doses by in silico analyses. Piperacillin/tazobactam (4/0.5 g, tid) was administered over 0.5 h. Blood samples were taken at 1, 4, and 7.5 h after the end of the infusion. Free piperacillin plasma concentrations were determined. Pharmacokinetic parameters and in silico analysis results were calculated using the freeware TDMx. The primary target was defined as percentage of the day (fT>1xMIC; fT>4xMIC) when piperacillin concentrations exceeded 1xMIC/4xMIC (minimum inhibitory concentration), considering a MIC breakpoint of 16 mg/L for Pseudomonas aeruginosa. In an off-label approach, two burn patients were treated with 8/1 g piperacillin/tazobactam, 3 h qid. fT>1xMIC (55 ± 22% vs. 77 ± 24%) and fT>4xMIC (17 ± 11% vs. 30 ± 11%) were lower in burn than in ICU patients after 4/0.5 g, 0.5 h, tid. In silico analyses indicated that fT>1xMIC (93 ± 12% burn, 97 ± 4% ICU) and fT>4xMIC (62 ± 23% burn, 84 ± 19% ICU) values increase by raising the piperacillin dosage to 8/1 g qid and prolonging the infusion time to 3 h. Off-label treatment results were similar to in silico data for burn patients (84%fT>1xMIC and 47%fT>4xMIC). Standard dosage regimens for piperacillin/tazobactam resulted in subtherapeutic piperacillin concentrations in burn and ICU patients. Dose adjustments via in silico analyses can help to optimize antibiotic therapy and to predict respective concentrations in vivo. Trial registration: NCT03335137, registered 07.11.2017, retrospectively.


Asunto(s)
Antibacterianos/farmacocinética , Quemaduras/sangre , Combinación Piperacilina y Tazobactam/farmacocinética , Adulto , Anciano , Anciano de 80 o más Años , Antibacterianos/sangre , Antibacterianos/farmacología , Bacterias/efectos de los fármacos , Quemaduras/tratamiento farmacológico , Quemaduras/microbiología , Femenino , Humanos , Masculino , Persona de Mediana Edad , Combinación Piperacilina y Tazobactam/sangre , Combinación Piperacilina y Tazobactam/farmacología , Esputo/microbiología
16.
J Endocrinol ; 2018 Oct 01.
Artículo en Inglés | MEDLINE | ID: mdl-30400045

RESUMEN

Based on findings that treatment with AT1 receptor blocker (ARB) prevents diet-induced obesity and that the activity of the hypothalamic-pituitary-adrenal (HPA) axis is stimulated by AngII and blocked by ARBs, we aimed to investigate whether ARB treatment can reduce stress-induced eating of cafeteria diet (CD) , thus contributing to alterations in eating behavior. Sprague Dawley rats were fed with chow or CD and treated with telmisartan (TEL, 8mg/kg/d) or vehicle. At weeks 2 and 12, rats were stressed over 5 consecutive days by restraint stress (RS, 4h) and by additional shaking at d5. Tail blood was sampled during RS to determine hormone levels. During the first period of RS, ACTH and corticosterone responses were diminished at d5 in CD- compared to chow-fed rats. Independently of feeding, TEL did not reduce stress hormones. Compared to food behavior before RS, the stress-induced CD eating increased in controls but remained unchanged in TEL-treated rats. After 12 weeks, TEL reduced weight gain and energy intake, particularly in CD-fed rats. Similar to the first RS period, corticosterone response was reduced in CD-fed rats at d5 during the second RS period. TEL did not further reduce stress hormones and did not lessen the CD eating upon RS. We conclude that CD feeding compensates for stress reactions. However, stress-induced CD eating was only reduced by TEL after short-term, but not after long-term drug treatment. Thus, the potency of ARBs to lower HPA activity only plays a minor role in reducing energy intake to prevent obesity.

17.
Curr Eye Res ; 43(1): 135-146, 2018 01.
Artículo en Inglés | MEDLINE | ID: mdl-28972410

RESUMEN

PURPOSE: Accumulation of lipoprotein-derived lipids including esterified and unesterified cholesterol in Bruch's membrane of human eyes is a major age-related change involved in initiating and sustaining soft drusen in age-related macular degeneration (AMD). The apolipoprotein (apo) A-I mimetic peptide 4F is a small anti-inflammatory and anti-atherogenic agent, and potent modifier of plasma membranes. We evaluated the effect of intravitreally-injected 4F on murine Bruch's membrane. METHODS: We tested single intravitreal injections of 4F doses (0.6 µg, 1.2 µg, 2.4 µg, and placebo scrambled peptide) in ApoEnull mice ≥10 months of age. After 30 days, mice were euthanized. Eyes were processed for either direct immunofluorescence detection of esterified cholesterol (EC) in Bruch's membrane whole mounts via a perfringolysin O-based marker linked to green fluorescent protein or by transmission electron microscopic visualization of Bruch's membrane integrity. Fluorescein isothiocyanate-conjugated 4F was traced after injection. RESULTS: All injected eyes showed a dose-dependent reduction of Bruch's membrane EC with a concomitant ultrastructural improvement compared to placebo treated eyes. At a 2.4 µg dose of 4F, EC was reduced on average by ~60% and Bruch's membrane returned to a regular pentalaminar structure and thickness. Tracer studies confirmed that injected 4F reached intraocular targets. CONCLUSION: We demonstrated a highly effective pharmacological reduction of EC and restoration of Bruch's membrane ultrastructure. The apoA-I mimetic peptide 4F is a novel way to treat a critical AMD disease process and thus represents a new candidate for treating the underlying cause of AMD.


Asunto(s)
Lámina Basal de la Coroides/metabolismo , Lípidos , Degeneración Macular/tratamiento farmacológico , Péptidos/farmacocinética , Animales , Lámina Basal de la Coroides/efectos de los fármacos , Lámina Basal de la Coroides/ultraestructura , Inyecciones Intravítreas , Degeneración Macular/metabolismo , Degeneración Macular/patología , Ratones , Microscopía Electrónica de Transmisión , Péptidos/administración & dosificación , Epitelio Pigmentado Ocular/efectos de los fármacos , Epitelio Pigmentado Ocular/metabolismo , Epitelio Pigmentado Ocular/ultraestructura
18.
Brain Res ; 1184: 160-7, 2007 Dec 12.
Artículo en Inglés | MEDLINE | ID: mdl-17945204

RESUMEN

Diabetes is often accompanied by a dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis which is regulated centrally via glucocorticoid (GR) and mineralocorticoid receptors (MR). Here, we compared the expression of both receptor subtypes in the brain of Zucker fatty and Zucker diabetic fatty (ZDF) rats together with their respective control rats. Both strains are primarily leptin resistant due to a mutated leptin receptor; ZDF rats, however, develop type-2 like diabetes. Using quantitative real-time PCR (qPCR) we found increased hypothalamic corticotrophin releasing hormone (CRH) levels in rats with the genetic ZDF background independently from leptin resistance. This was accompanied by elevated plasma corticosterone levels and by a higher reactivity of the HPA axis in response to CRH. Rats with the genetic ZDF background showed increased mRNA levels of GR in the amygdala and hypothalamus and increased mRNA levels of MR in the hippocampus and hypothalamus compared to rats with the Zucker fatty background. In leptin resistant ZDF rats but not in Zucker fatty rats, the mRNA levels of MR were selectively increased in the amygdala compared to nondiabetic control rats. No differences in the GR mRNA levels were found between leptin resistant Zucker fatty rats and lean control rats. Thus, an increased drive of the HPA axis in rats with ZDF background is associated with a differential expression of GR and MR in the limbic system. This dysregulation of the HPA axis may eventually lead, in combination with leptin resistance, to the development of diabetes in ZDF rats.


Asunto(s)
Diabetes Mellitus Tipo 2/patología , Expresión Génica/fisiología , Sistema Límbico/fisiopatología , Receptores de Glucocorticoides/metabolismo , Receptores de Mineralocorticoides/metabolismo , Análisis de Varianza , Animales , Área Bajo la Curva , Glucemia/metabolismo , Peso Corporal/fisiología , Corticosterona/sangre , Hormona Liberadora de Corticotropina/metabolismo , Diabetes Mellitus Tipo 2/sangre , Diabetes Mellitus Tipo 2/metabolismo , Modelos Animales de Enfermedad , Insulina/metabolismo , Leptina/metabolismo , Masculino , Ratas , Ratas Zucker , Receptores de Glucocorticoides/genética , Receptores de Mineralocorticoides/genética
19.
J Endocrinol ; 235(3): 251-265, 2017 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-28970286

RESUMEN

Aldosterone has been identified as an important factor in obesity-associated hypertension. Here, we investigated whether sphingosine-1-phosphate (S1P), which has previously been linked to obesity, increases aldosterone release. S1P-induced aldosterone release was determined in NCI H295R cells in the presence of S1P receptor (S1PR) antagonists. In vivo release of S1P (100-300 µg/kgbw) was investigated in pithed, lean Sprague Dawley (SD) rats, diet-obese spontaneous hypertensive rats (SHRs), as well as in lean or obese Zucker rats. Aldosterone secretion was increased in NCI H295R cells by S1P, the selective S1PR1 agonist SEW2871 and the selective S1PR2 antagonist JTE013. Treatment with the S1PR1 antagonist W146 or fingolimod and the S1PR1/3 antagonist VPbib2319 decreased baseline and/or S1P-stimulated aldosterone release. Compared to saline-treated SD rats, plasma aldosterone increased by ~50 pg/mL after infusing S1P. Baseline levels of S1P and aldosterone were higher in obese than in lean SHRs. Adrenal S1PR expression did not differ between chow- or CD-fed rats that had the highest S1PR1 and lowest S1PR4 levels. S1P induced a short-lasting increase in plasma aldosterone in obese, but not in lean SHRs. However, 2-ANOVA did not demonstrate any difference between lean and obese rats. S1P-induced aldosterone release was also similar between obese and lean Zucker rats. We conclude that S1P is a local regulator of aldosterone production. S1PR1 agonism induces an increase in aldosterone secretion, while stimulating adrenal S1PR2 receptor suppresses aldosterone production. A significant role of S1P in influencing aldosterone secretion in states of obesity seems unlikely.


Asunto(s)
Aldosterona/metabolismo , Lisofosfolípidos/fisiología , Obesidad/metabolismo , Receptores de Lisoesfingolípidos/fisiología , Esfingosina/análogos & derivados , Animales , Dieta Alta en Grasa , Humanos , Lisofosfolípidos/metabolismo , Masculino , Obesidad/sangre , Obesidad/etiología , Ratas , Ratas Endogámicas SHR , Ratas Sprague-Dawley , Ratas Zucker , Receptores de Lisoesfingolípidos/metabolismo , Transducción de Señal/fisiología , Esfingosina/metabolismo , Esfingosina/fisiología , Células Tumorales Cultivadas
20.
Naunyn Schmiedebergs Arch Pharmacol ; 390(5): 505-518, 2017 May.
Artículo en Inglés | MEDLINE | ID: mdl-28144709

RESUMEN

AT1 blockers (ARB) prevent diabetes by improving pancreatic ß cell function. Less is known about whether α cells are affected although they express angiotensin II (AngII) receptors. We aimed to investigate glucagon release upon AngII stimulation. We determined glucagon release after AngII stimulation (0.01-100 µM) in α cells (InR1G9) and isolated murine islets. We determined plasma glucagon in rats that were chronically treated with AngII (9 µg/h) or the ARBs telmisartan (8 mg/kg/day) and candesartan (16 mg/kg/day) and correlated glucagon with additional hormones (e.g. leptin). Glucagon was only released from InR1G9 cells and islets at the highest AngII concentrations (>10 µM). This was not inhibited by losartan or PD123319. Ang(1-7) and AngIV were also almost ineffective. AngII did not alter glucagon secretion from islets. Plasma glucagon increased when obese Zucker rats were treated with AngII or candesartan and also when Sprague Dawley rats were treated with telmisartan in parallel to high-calorie feeding. Plasma glucagon and leptin negatively correlated in ARB-treated rats. The glucagon release from InR1G9 cells or islets after AngII, AngIV or Ang(1-7) is unspecific since it only occurs, if at all, after the highest concentrations and cannot be blocked by specific inhibitors. Thus, the AngII-dependent increase in plasma glucagon seems to be mediated by indirect mechanisms. The negative correlations between plasma leptin and glucagon confirm findings showing that leptin suppresses glucagon release, leading us to suppose that the increase in plasma glucagon is related to the decrease in leptin after ARB treatment.


Asunto(s)
Bloqueadores del Receptor Tipo 1 de Angiotensina II/farmacología , Angiotensina II/metabolismo , Bencimidazoles/farmacología , Benzoatos/farmacología , Glucagón/metabolismo , Hipoglucemiantes/farmacología , Islotes Pancreáticos/efectos de los fármacos , Leptina/metabolismo , Tetrazoles/farmacología , Animales , Compuestos de Bifenilo , Línea Celular , Relación Dosis-Respuesta a Droga , Glucagón/sangre , Islotes Pancreáticos/metabolismo , Leptina/sangre , Masculino , Ratones Endogámicos C57BL , Ratas Sprague-Dawley , Ratas Zucker , Receptor de Angiotensina Tipo 1/efectos de los fármacos , Receptor de Angiotensina Tipo 1/genética , Receptor de Angiotensina Tipo 1/metabolismo , Telmisartán , Factores de Tiempo , Regulación hacia Arriba
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