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Papers by Silvia Garcia

Journal of Endocrinology, 2000

The human glioblastoma-astrocytoma cell line U-373-MG shows morphological features typical of its... more The human glioblastoma-astrocytoma cell line U-373-MG shows morphological features typical of its neuroectodermal origin. Cells showed positive immunostaining for the glial fibrillary acidic protein. We used this cell culture for studying the putative production of TRH and TRH-related peptides. In a cell extract and conditioned medium, cation and anion exchange chromatography and HPLC revealed the presence of TRH and acidic TRH-like peptides which were identified, at least in part, as pGlu-Glu-ProNH(2). These findings demonstrated that U-373-MG cells are able to produce and release these peptides. Further evidence of TRH synthesis was obtained by amplification using RT-PCR of a 396 bp fragment that corresponds to the TRH precursor mRNA. Our results therefore suggest that the U-373-MG cell line may be a useful model for studying the regulation of TRH and TRH-related peptide production and the interaction of these peptides with other classical neurotransmitter systems. In fact, piloca...

Hypertension, 2000

P202 Thyroliberin (TRH) participates in central cardiovascular regulation and hypothalamic TRH pr... more P202 Thyroliberin (TRH) participates in central cardiovascular regulation and hypothalamic TRH precursor gene overexpression induces hypertension which can be reversed by antisense (AS) treatment. SHR show an increased central TRH synthesis and release and TRH receptor number. We show here that a phosphotioate AS against the preTRH injected icv decreased the augmented diencephalic TRH content (ng/mg protein) along with a normalization of systolic blood pressure (SABP) at 24-48 hs in SHR without effect in normotensive WKY rats (table). Saline or sense treatment had no effects. To investigate if changes in thyroid function may explain these results, we studied plasma TSH, T 3 (ng/ml) and T 4 (ug%) in control (CON) and AS-treated WKY and SHR. Although TSH was elevated in SHR compared to WKY rats in basal conditions and AS reverted it (table), no differences (n=5) were observed between strains with or without AS treatment in plasma T 4 (CON; WKY: 5.0±0.4 vs SHR: 5.3±0.5 and AS; WKY:5.4±...

Journal of Cardiac Failure, 2021

Cardiac thyrotropin-releasing hormone (TRH) inhibition improves ventricular function and reduces ... more Cardiac thyrotropin-releasing hormone (TRH) inhibition improves ventricular function and reduces hypertrophy and fibrosis after myocardial infarction in rats.

Journal of molecular and cellular cardiology, Jan 26, 2018

Cardiac tyhrotropin-releasing hormone (TRH) is overexpressed in the hypertrophied left ventricle ... more Cardiac tyhrotropin-releasing hormone (TRH) is overexpressed in the hypertrophied left ventricle (LV) of spontaneously hypertensive rats (SHR) and its inhibition prevents both hypertrophy and fibrosis. In a normal heart, the TRH increase induces fibrosis and hypertrophy opening the question of whether TRH could be a common mediator of left ventricular hypertrophy (LVH). We used angiotensin II (AngII) as an inductor of LVH to evaluate if the blockade of LV-TRH prevents hypertrophy and fibrosis in mice. We challenged C57BL/6 adult male mice with an infusion of AngII (osmotic pumps; 2 mg/kg.day) to induce LVH. Groups of mice were injected with an intracardiac siRNA-TRH or scrambled siRNA (siRNA-Con). Body weight, water intake and systolic arterial blood pressure (SABP) were measured daily. AngII significantly increased water intake and SABP (p < .05). Cardiac hypertrophy (heart weight/body weight) was evident in the group with the normal cardiac TRH system. In fact, it was found an ...

Obesity, 2009

We explored peroxisome proliferator‐activated receptor‐γ co‐activator 1α gene (PPARGC1A), peroxis... more We explored peroxisome proliferator‐activated receptor‐γ co‐activator 1α gene (PPARGC1A), peroxisome proliferator‐activated receptor‐γ gene (PPARG), and transcription factor A mitochondrial gene (Tfam) promoter DNA methylation in newborns between both extremes of abnormal fetal growth: Small (SGA) and large for gestational age (LGA) in relation to the mother's characteristics. We further sought for the association of rs9930506 variant at FTO gene and the promoter patterns of DNA methylation in the aforementioned genes, in relation to the offspring's birth weight. In a cross‐sectional study, 88 healthy pregnant women and their babies were included. According to the offspring birth weight, there were 57 newborns with appropriate weight for gestational age (AGA), 17 SGA, and 14 LGA. After bisulphite treatment of umbilical cord genomic DNA, a real‐time methylation‐specific PCR was used to determine the promoter methylation status in selected CpGs. Promoter methylated DNA/unmethy...

Neuroscience Letters, 1992

A two week administration of the glucocorticoid betametasone to male Wistar rats produced a mild ... more A two week administration of the glucocorticoid betametasone to male Wistar rats produced a mild hypertensive state. The brain of these rats showed some significant changes in amine and metabolite content with respect to normotensive controls. Epinephrine and metanephrine were increased in the rostral ventrolateral medulla and in the preoptic area. Epinephrine also increased in the septal area. Normetanephrine decreased in the rostral ventrolateral medulla. Dopamine and homovanillic acid increased in septal and preoptic areas. Dopamine alone increased in rostral ventrolateral medulla. Serotonin and 5-hydroxyindole-3-acetic acid increased in the septal area and dorsal medulla. These changes suggest significant alterations in the aminergic activity of the brain circuitry known to regulate cardiovascular functions; the changes may play a basic role in the development and maintenance of glucocorticoid-induced hypertension.

Journal of Human Hypertension, 2003

Clinical and Experimental Hypertension, 2005

Normal mammary gland epithelial cells and breast cancer cells express the calcium-sensing recepto... more Normal mammary gland epithelial cells and breast cancer cells express the calcium-sensing receptor (CaSR), which is the master regulator of systemic calcium metabolism. During lactation, activation of the CaSR in mammary epithelial cells downregulates parathyroid hormone-related protein (PTHrP) levels in milk and in the circulation, and increases calcium transport into milk. However, very little information is available on the role of CaSR in goat mammary gland epithelial cells (GMECs) apoptosis. In this investigation, the full-length cDNA of CaSR from Xinong Saanen dairy goats was cloned, which contains an open-reading frame of 3,258 bp encoding 1,085 amino acids with a predicted molecular weight of 121.0 kDa and an isoelectric point of 5.65. The amino acid sequence is highly homologous with sheep, and the goat CaSR gene is mapped to chromosome 1. Quantitative realtime PCR suggested that CaSR was predominantly expressed in the heart, kidney and mammary gland. Then, we found the stimulation of CaSR with its activator gadolinium chloride (GdCl 3) contributed to increase CaSR mRNA levels in GMECs and simultaneously promoted cell apoptosis, and these effects were abrogated partially by NPS2390 which is an inhibitor of CaSR. We also demonstrated that Ca 2? increased CaSR mRNA levels and induced GMECs apoptosis and restrained cell proliferation. In contrast, PTHrP overexpression protected GMECs from calcium-induced apoptosis, and promoted cell proliferation. In conclusion, these results suggest that PTHrP overexpression protects GMECs from CaSR activationinduced apoptosis.

Hypertension, 2008

et al 1 reported that endogenous melanocortin may cause elevation of arterial blood pressure (ABP... more et al 1 reported that endogenous melanocortin may cause elevation of arterial blood pressure (ABP) in spontaneously hypertensive rats. We invite authors to consider that the hypothalamic thyrotropin-releasing hormone (TRH) system may be involved, because spontaneously hypertensive rats show an hyperactivity of this system, 2 and intracerebroventricular (ICV) injections of a prepro-TRH antisense oligonucleotide (AS) decreases both elevated TRH content and ABP independent of thyroid status. 3 Leptin effects include increases in sympathetic activity and inhibition of the starvation-induced suppression of thyroid hormones apparently by upregulating prepro-TRH gene expression. Then, leptin can increase the MC4R ligand (␣-melanocytestimulating hormone) production to regulate TRH expression. 4 Furthermore, we have shown that ICV leptin injections induce a pressor effect that is avoided by prepro-TRH AS pretreatment. 5 Hence, we proposed that melanocortin activity may raise ABP through TRH activation, and we report here that, in Wistar rats, the MCR4 agonist (␣-melanocyte-stimulating hormone agonist [MTII])-induced elevation of ABP can be blocked by 24-hour ICV pretreatment with prepro-TRH AS. Wistar rats were implanted with a guided canula into the III ventricle for MTII, AS, or saline infusion (V) as described elsewhere. 5 Carotid artery was cannulated for mean ABP measurements. We measured body weight and food consumption in basal condition and 24 hours after ICV injection in awake animals with (ICV 1) vehicle (V), AS (150 g), and oligonucleotide with the inverted AS sequence (150 g) as a control. After another 24 hours we performed a second injection (ICV 2) with V or MTII (0.6 nmol). Animals were then euthanized and the hypothalamus was removed to measure TRH (radioimmunoassay). As expected, MTII induces a decrease in food consumption and body weight. MTII also produced increases of mean ABP and hypothalamic TRH in rats treated with MTII, whereas AS pretreatment prevented both increases. MTII action was not reversed by the AS inverted sequence (Table). In conclusion, we show that the melanocortin 3 and 4 agonist induced hypertension only in the presence of an intact hypothalamic TRH system; thus, we propose that an activation of the axis leptin-melanocortin-TRH might explain increases of ABP in this genetic model of hypertension.

American Journal of Hypertension, 2003

White coat hypertension is frequently found in pediatric hypertensive patients. 45% of hypertensi... more White coat hypertension is frequently found in pediatric hypertensive patients. 45% of hypertensive adolescents attending our clinic were white coat hypertensive and all of them were offspring of essential hypertensive parents. Family history of hypertension and blood pressure in early life are major predictors of hypertension in adulthood. Therefore, the aim of this study was to evaluate if isolated office high blood pressure is associated to other risk factors reported in essential hypertension, such as microalbuminuria and gene alleles related to essential hypertension. In 311 adolescent offspring of hypertensive parents: 180 normotensive (N) (age 13 Ϯ 2.9, BMI 24.8 Ϯ 5.7, 114 males); 60 white coat hypertensives (WCH) (age 13.6 Ϯ 2.3, BMI 23.3 Ϯ 6.4, 31 males); and 71 essential hypertensives (EH) age 13.3 Ϯ 2.9, BMI 24.1 Ϯ 5.6, 53 males) we evaluated microalbumine excretion in a 24 hour urine collection, and polimorphisms of the renin-angiotensin-aldosterone system gene components: ECA (I/D), M235T and T174M of the angiotensinogen gene (AGT), AT1R (A1166C) and CYP11b2 (C344T) by PCR/RFLP/ASO.

American Journal of Hypertension, 2001

the roles and efficacy of pharmacologic and non-pharmacologic therapies.

American Journal of Hypertension, 2000

The underlying mechanism(s) by which ACE inhibitors cause cough might involved bradykinin pathway... more The underlying mechanism(s) by which ACE inhibitors cause cough might involved bradykinin pathways. A variant of bradykinin (B2) receptor could be an explanation of the potentiation of bradykinin inflammatory effects during ACE inhibitor therapy. Objective: To examine the relationship between the genetic polymorphism of bradykinin (B2) receptor (deletion of 9 pairs of bases on exon 1 of coding gene) and ACE inhibitor-cough. Methods: Subjects with a past history of ACE inhibitorcough, who were positively rechallenged during a filter period, were selected for the study. One hundred ninety-one patients with no cough while treated with an ACE inhibitor during at least 6 months were classified as control subjects. In all individuals the genomic DNA was isolated from peripheral leukocytes. Allelic polymorphisms were determined by polymerasechain-reaction (PCR) amplification and autoradiography. Results: Conclusion: Allelic polymorphism (ϩ/ϩ) of bradykinin (B2) receptor coding gene might be of clinical significance and be a useful predictor of ACE inhibitor-related cough.

Regulatory Peptides, 2005

Thyrotropin (TSH)-releasing hormone (TRH) also known as thyroliberin was the first of a number of... more Thyrotropin (TSH)-releasing hormone (TRH) also known as thyroliberin was the first of a number of peptides exerting several roles as a hormone and as a neuropeptide. Its ubiquitous distribution in the hypothalamus and in the extrahypothalamic regions and its diverse pharmacological and physiological effects are all features of its dual functions. For this reason, TRH has been the subject of much research throughout the past 20 years, work that has examined the structure, function, distribution, and regulation of the tripeptide and it has been extensively reviewed elsewhere [1,2] [

Pediatric Research, 2004

Obesity and hypertension are increasing medical problems in adolescents. We evaluated the associa... more Obesity and hypertension are increasing medical problems in adolescents. We evaluated the association between being overweight-particularly abdominal fat-and having hypertension and assessed the contribution of the Trp64Arg ␤ 3-adrenergic receptor gene variant. In a population-based study, we determined family history, anthropometric variables, and arterial blood pressure of 934 high school students, out of whom we selected 121 normotensive and 54 hypertensive students. Biochemical measurements included circulating renin and angiotensin-converting enzyme activities, leptin, glucose, insulin and lipid levels, and ␤ 3-adrenergic receptor genotypes. We used Mann-Whitney U test, 2-test, and Spearman rank-order correlation. In the total population, hypertension prevalence increased across the entire range of body mass index (BMI) percentiles. In the sample, hypertensive students showed higher BMI, waist-tohip ratio, triglycerides, and insulin resistance and lower HDLcholesterol than normotensive students did. Age-and sexadjusted systolic arterial blood pressure was correlated with BMI, waist-to-hip ratio, insulin resistance, and leptin. Leptin was correlated with BMI and homeostasis model assessment method. We found no association among hypertension, BMI, and leptin levels with ␤ 3-adrenergic receptor genotypes. Especially in girls, the waist-to-hip ratio was, however, suggestively higher in Arg64 variant carriers than in noncarriers, independent of hypertension. In fact, there was a significantly (p Ͻ 0.01) higher frequency of carriers of the Arg64 variant across the waist-to-hip ratio quartiles. In adolescents of European origin, hypertension is associated with an increased degree of obesity among other characteristics of the metabolic syndrome; the Trp64Arg variant of the ␤ 3-adrenergic receptor gene may favor the central adiposity gain. (Pediatr Res 55: 836-841, 2004) Abbreviations ␤ 3 AR, ␤ 3-adrenergic receptor ABP, arterial blood pressure BMI, body mass index HOMA, homeostasis model assessment method Trp64Arg, substitution of arginine for tryptophan at codon 64 WHR, waist-to-hip ratio

Journal of Neurochemistry, 2011

The renin-angiotensin system (RAS) is an essential regulator of blood pressure and fluid homeosta... more The renin-angiotensin system (RAS) is an essential regulator of blood pressure and fluid homeostasis. A complete and functional RAS exists in the brain and comprises all necessary precursors and enzymes required for the synthesis and metabolism of its components (Veerasingham and Raizada 2003; Xu et al. 2011). In addition to the known effector angiotensin (Ang) II, the heptapeptide Ang-(1-7) is a biologically active component of the RAS which limits the pressor and proliferative effects of Ang II. Thus, Ang-(1-7) produces vasodilation, natriuresis and diuresis, inhibits angiogenesis and cell growth (Ferrario et al. 2010; Ferreira et al. 2010; Xu et al. 2011). At the central level, Ang-(1-7) facilitates the baroreflex control of blood pressure and acts at cardioregulatory brain areas, such as hypothalamic and brainstem nuclei,

Journal of Endocrinology, 2006

Thyroid hormones play critical roles in differentiation, growth and metabolism, but their partici... more Thyroid hormones play critical roles in differentiation, growth and metabolism, but their participation in immune system regulation has not been completely elucidated. Modulation of in vivo thyroid status was used to carry out an integrative analysis of the role of the hypothalamus–pituitary–thyroid (HPT) axis in T and B lymphocyte activity. The participation of the protein kinase C (PKC) signaling pathway and the release of some cytokines upon antigenic stimulation were analyzed. Lymphocytes from hyperthyroid mice displayed higher T-and B-cell mitogen-induced proliferation, and those from hypothyroid mice displayed lower T- and B-cell mitogen-induced proliferation, compared with euthyroid animals. Reversion of hypothyroid state by triiodothyronine (T3) administration recovered the proliferative responses. No differences were found in lymphoid subset balance. Both total PKC content and mitogen-induced PKC translocation were higher in T and B cells from hyperthyroid mice, and lower i...

Frontiers in Bioscience, 2007

American journal of physiology. Heart and circulatory physiology, 2014

Thyrotropin-releasing hormone (TRH) hyperactivity has been observed in the left ventricle of spon... more Thyrotropin-releasing hormone (TRH) hyperactivity has been observed in the left ventricle of spontaneously hypertensive rats. Its long-term inhibition suppresses the development of hypertrophy, specifically preventing fibrosis. The presence of diverse systemic abnormalities in spontaneously hypertensive rat hearts has raised the question of whether specific TRH overexpression might be capable of inducing structural changes in favor of the hypertrophic phenotype in normal rat hearts. We produced TRH overexpression in normal rats by injecting into their left ventricular wall a plasmid driving expression of the preproTRH gene (PCMV-TRH). TRH content and expression of preproTRH, collagen type III, brain natriuretic peptide, β-myosin heavy chain, Bax-to-Bcl-2 ratio, and caspase-3 were measured. The overexpression maneuver was a success, as we found a significant increase in both tripeptide and preproTRH mRNA levels in the PCMV-TRH group compared with the control group. Immunohistochemica...

Hypertension, 2002

Leptin, an adipocyte-released hormone, modifies food intake and energy expenditure regulating hyp... more Leptin, an adipocyte-released hormone, modifies food intake and energy expenditure regulating hypothalamicpituitary-thyroid axis function. We previously reported that thyrotropin-releasing hormone (TRH) precursor gene overexpression induces hypertension in the normal rat and that spontaneously hypertensive rats have central TRH hyperactivity with increased TRH synthesis and release and an elevated TRH receptor number. In both models, intracerebroventricular antisense (AS) treatment against the TRH precursor produced a dose-dependent reduction of the increased diencephalic TRH content while normalizing high arterial blood pressure. In this article, we report that male Wistar rats that were made hypertensive by intracerebroventricular injection of a eucaryotic expression plasmid containing the pre-TRH cDNA showed decreased leptin plasma levels and that pre-TRH AS treatment reversed this phenomenon. In addition, male and female spontaneously hypertensive rats showed lower levels of circulating leptin than did sex-matched Wistar-Kyoto control rats. This difference also was abated by the pre-TRH AS treatment. Conversely, 20 g ICV leptin induced a long-lasting pressor effect (18Ϯ5 mm Hg, nϭ6, PϽ0.01, Ͼ60 minutes) that was not observed in pre-TRH AS pretreated rats (2Ϯ3 mm Hg, nϭ6) but persisted in rats used as controls that were treated with inverted oligonucleotide (20Ϯ6 mm Hg, nϭ4, PϽ0.01). These data suggest that in rats with TRH-induced hypertension, leptin is decreased, inducing compensatory adiposity. We propose that because leptin produces central TRH synthesis and release, obesity may induce hypertension through TRH system activation and that the TRH-leptin interaction may thus contribute to the strong association between hypertension and obesity. (Hypertension. 2002; 39[part 2]:491-495.