Global identification of the genes and pathways differentially expressed in hypothalamus in early and established neurogenic hypertension

Marques, Francine Z.; Campain, Anna; Davern, Pamela J.; Yang, Yee Hwa; Head, Geoffrey A.; Morris, Brian J.

doi:10.1152/physiolgenomics.00009.2011

Cited by 29 publications

(32 citation statements)

References 49 publications

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“…44 An SNP in close proximity to the SMARCA and VLDLR genes (rs872256) was genome-wide associated with SBP during the pubertal epoch. SMARCA is a member of the SWI/SNF family of proteins and is highly similar to the brahma protein, where it has been hypothesized that cardiac hypertrophy and the fetal gene expression program are associated with distinguishable binding of brahma and SMARCA4 on genes.…”

Section: Discussionmentioning

confidence: 99%

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International Genome-Wide Association Study Consortium Identifies Novel Loci Associated With Blood Pressure in Children and Adolescents

Parmar¹,

Taal²,

Timpson³

et al. 2016

Circ Cardiovasc Genet

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266S ystolic and diastolic blood pressure (SBP and DBP) are complex phenotypes, with known environmental and genetic risk factors.1 Elevated SBP and DBP are associated with premature mortality 2,3 and cardiovascular diseases. 2,4-9 Clinical Perspective on p 278Recent genome-wide association studies (GWAS) have identified genetic variants associated with adult SBP and DBP and hypertension. [10][11][12][13][14][15][16][17][18][19][20][21][22][23][24] Several of these loci are in biologically plausible candidate genes, for example, those that influence the renin-angiotensin system. 25 There are established patterns of age-related changes in BP in industrialized populations, which support a potential interaction of genetic variants with age-related changes to environmental exposures in these populations. 26,27 For genetic variants that directly modulate childhood BP, effects might change with age, might differ between developmental periods (early life, childhood, and adolescence), and might also differ to those variants that act in adulthood.Children and adolescents are rarely treated with antihypertensives, whereas from middle age onwards, an increasing proportion of adults are using such medications. 26 Consequently, it is easier to examine genetic variants that are associated with untreated SBP and DBP in children. Variation in SBP, and to Background-Our aim was to identify genetic variants associated with blood pressure (BP) in childhood and adolescence. Methods and Results-Genome-wide association study data from participating European ancestry cohorts of the EarlyGenetics and Lifecourse Epidemiology (EAGLE) Consortium was meta-analyzed across 3 epochs; prepuberty (4-7 years), puberty (8-12 years), and postpuberty (13-20 years). Two novel loci were identified as having genome-wide associations with systolic BP across specific age epochs: rs1563894 (ITGA11, located in active H3K27Ac mark and transcription factor chromatin immunoprecipitation and 5′-C-phosphate-G-3′ methylation site) during prepuberty (P=2.86×10-8) and rs872256 during puberty (P=8.67×10 -9 ). Several single-nucleotide polymorphism clusters were also associated with childhood BP at P<5×10 -3. Using a P value threshold of <5×10 -3 , we found some overlap in variants across the different age epochs within our study and between several single-nucleotide polymorphisms in any of the 3 epochs and adult BPrelated single-nucleotide polymorphisms. Conclusions-Our results suggest that genetic determinants of BP act from childhood, develop over the lifecourse, and show some evidence of age-specific effects. Parmar et al Blood Pressure GWAS in Children 267a lesser extent DBP, in adolescence and early adulthood is associated with subsequent adult risk of coronary heart disease and stroke. 28,29 Understanding the risk factors, including genetic variation, that are associated with SBP and DBP through childhood and into adolescence may therefore inform an improved understanding of the life course pathogenesis of adult hypertension and cardiovascular disease...

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Section: Discussionmentioning

confidence: 99%

“…NPY exerts marked portal hypotensive effects and ameliorates the hyperdynamic circulation in cirrhotic ascitic rats 43 . Comparison of profiles of young and adult BPH/2J mice, after adjusting for maturation genes identified NPY as potentially causative mechanisms involved in hypertension etiology and maintenance in the hypothalamus 44 .…”

Section: Studymentioning

confidence: 99%

International Genome-Wide Association Study Consortium Identifies Novel Loci Associated With Blood Pressure in Children and Adolescents

Parmar¹,

Taal²,

Timpson³

et al. 2016

Circ Cardiovasc Genet

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“…Thus, hcrt could potentially contribute to the development and maintenance of BPH/2J hypertension. 5 Furthermore, BPH/2J mice have ≈4-fold greater expression of the hcrt gene in the hypothalamus during the dark-active period compared with light period when mice are predominantly inactive or asleep. 6 Characteristics of the BPH/2J mouse strain, such as high BP, tachycardia, greater locomotor activity, overactivity of the SNS, 2 and exaggerated cardiovascular reactivity to stressful stimuli, 7 could all be reflective of a greater activity of the orexinergic neurons.…”

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confidence: 98%

“…5,6 An important finding was that expression of the orexin precursor gene (hcrt) in BPH/2J mice was more than double that of normotensive mice in early and established hypertension. Thus, hcrt could potentially contribute to the development and maintenance of BPH/2J hypertension.…”

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Contribution of Orexin to the Neurogenic Hypertension in BPH/2J Mice

et al. 2016

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BPH/2J mice are a genetic model of hypertension which were selectively bred for elevated blood pressure (BP) in the 1970s alongside a normotensive strain (BPN/3J).1 Recent studies suggest that the hypertension in BPH/2J mice is caused by enhanced activation of the sympathetic nervous system (SNS) because ganglion blockade causes a greater depressor response in BPH/2J mice compared with BPN/3J controls. 2,3 Importantly, cardiovascular regulatory forebrain regions within the hypothalamus and amygdala display markedly greater neuronal activity in BPH/2J compared with BPN/3J mice during the dark-active period of the 24-hour light cycle.2 Furthermore, lesions of the medial amygdala reduced the hypertension and SNS overactivity in BPH/2J mice. 4 Thus the central nervous system seems to play a crucial role in driving the sympathetically mediated hypertension in this model.A gene array approach has been used to identify differential expression of genes in the hypothalamus between BPH/2J and BPN/3J mice. 5,6 An important finding was that expression of the orexin precursor gene (hcrt) in BPH/2J mice was more than double that of normotensive mice in early and established hypertension. Thus, hcrt could potentially contribute to the development and maintenance of BPH/2J hypertension.5 Furthermore, BPH/2J mice have ≈4-fold greater expression of the hcrt gene in the hypothalamus during the dark-active period compared with light period when mice are predominantly inactive or asleep. 6 Characteristics of the BPH/2J mouse strain, such as high BP, tachycardia, greater locomotor activity, overactivity of the SNS, 2 and exaggerated cardiovascular reactivity to stressful stimuli, 7 could all be reflective of a greater activity of the orexinergic neurons. Indeed, orexin is capable of increasing BP, heart rate (HR), and SNS activity.8 Orexinergic neurons originate in the hypothalamus and project to a wide range of brain regions, but in terms of sympathetic control of BP, the Abstract-BPH/2J mice are a genetic model of hypertension associated with an overactive sympathetic nervous system.Orexin is a neuropeptide which influences sympathetic activity and blood pressure. Orexin precursor mRNA expression is greater in hypothalamic tissue of BPH/2J compared with normotensive BPN/3J mice. To determine whether enhanced orexinergic signaling contributes to the hypertension, BPH/2J and BPN/3J mice were preimplanted with radiotelemetry probes to compare blood pressure 1 hour before and 5 hours after administration of almorexant, an orexin receptor antagonist. Mid frequency mean arterial pressure power and the depressor response to ganglion blockade were also used as indicators of sympathetic nervous system activity. Administration of almorexant at 100 (IP) and 300 mg/ kg (oral) in BPH/2J mice during the dark-active period (2 hours after lights off) markedly reduced blood pressure (−16.1±1.6 and −11.0±1.1 mm Hg, respectively; P<0.001 compared with vehicle). However, when almorexant (100 mg/ kg, IP) was administered during the light-inactive pe...

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“…This revealed differences in early and established hypertension in levels of transcripts encoding proteins having effects on sympathetic outflow as well as inflammation and stress responses. 111 In order to identify transcripts corresponding to the exaggerated waking BP surge (that is a risk factor myocardial infarction and stroke) we obtained array data for the diurnal BP peak and trough. 112 This implicated hypothalamic transcripts encoding known BP regulators, as well as novel proteins involved in inflammation, mitochondrial function, and other pathways.…”

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confidence: 99%