Integrated Computational and Experimental Analysis of the Neuroendocrine Transcriptome in Genetic Hypertension Identifies Novel Control Points for the Cardiometabolic Syndrome

Friese, Ryan S.; Yuan, Chun; Nievergelt, Caroline M.; Schork, Andrew J.; Mahapatra, Nitish R.; Rao, Fangwen; Napolitan, Philip S; Waalen, Jill; Ehret, Georg; Munroe, Patricia B.; Schmid‐Schönbein, Geert W.; Eskin, Eleazar; O’Connor, Daniel T.

doi:10.1161/circgenetics.111.962415

Cited by 6 publications

(4 citation statements)

References 44 publications

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“…Further analysis of human population indicated that a single nucleotide polymorphism of Yy1 was associated with BP, body mass index, and fasting glucose. They suggested this gene as the strongest candidate influencing hypertension and metabolic syndrome (Friese et al, 2012).…”

Section: Molecular Contributions To Hypertension In Bph/2 Micementioning

confidence: 99%

Mechanisms Responsible for Genetic Hypertension in Schlager BPH/2 Mice

et al. 2019

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It has been 45 years since Gunther Schlager used a cross breeding program in mice to develop inbred strains with high, normal, and low blood pressure (BPH/2, BPN/3, and BPL/1 respectively). Thus, it is timely to gather together the studies that have characterized and explored the mechanisms associated with the hypertension to take stock of exactly what is known and what remains to be determined. Growing evidence supports the notion that the mechanism of hypertension in BPH/2 mice is predominantly neurogenic with some of the early studies showing aberrant brain noradrenaline levels in BPH/2 compared with BPN/3. Analysis of the adrenal gland using microarray suggested an association with the activity of the sympathetic nervous system. Indeed, in support of this, there is a larger depressor response to ganglion blockade, which reduced blood pressure in BPH/2 mice to the same level as BPN/3 mice. Greater renal tyrosine hydroxylase staining and greater renal noradrenaline levels in BPH/2 mice suggest sympathetic hyperinnervation of the kidney. Renal denervation markedly reduced the blood pressure in BPH/2 but not BPN/3 mice, confirming the importance of renal sympathetic nervous activity contributing to the hypertension. Further, there is an important contribution to the hypertension from miR-181a and renal renin in this strain. BPH/2 mice also display greater neuronal activity of amygdalo-hypothalamic cardiovascular regulatory regions. Lesions of the medial nucleus of the amygdala reduced the hypertension in BPH/2 mice and abolished the strain difference in the effect of ganglion blockade, suggesting a sympathetic mechanism. Further studies suggest that aberrant GABAergic inhibition may play a role since BPH/2 mice have low GABAA receptor δ, α4 and β2 subunit mRNA expression in the hypothalamus, which are predominantly involved in promoting tonic neuronal inhibition. Allopregnanolone, an allosteric modulator of GABAA receptors, which increase the expression of these subunits in the amygdala and hypothalamus, is shown to reduce the hypertension and sympathetic nervous system contribution in BPH/2 mice. Thus far, evidence suggests that BPH/2 mice have aberrant GABAergic inhibition, which drives neuronal overactivity within amygdalo-hypothalamic brain regions. This overactivity is responsible for the greater sympathetic contribution to the hypertension in BPH/2 mice, thus making this an ideal model of neurogenic hypertension.

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Section: Molecular Contributions To Hypertension In Bph/2 Micementioning

confidence: 99%

Mechanisms Responsible for Genetic Hypertension in Schlager BPH/2 Mice

et al. 2019

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“…Different animal models of arterial hypertension help to analyze the transcriptome of the adrenal glands and to uncover common genetic mechanisms of hypertension across mammalian species that might, therefore, be pertinent to human hypertension too [3, 4, 6]. …”

Section: Introductionmentioning

confidence: 99%

Molecular determinants of the adrenal gland functioning related to stress-sensitive hypertension in ISIAH rats

et al. 2016

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BackgroundThe adrenals are known as an important link in pathogenesis of arterial hypertensive disease. The study was directed to the adrenal transcriptome analysis in ISIAH rats with stress-sensitive arterial hypertension and predominant involvement in pathogenesis of the hypothalamic-pituitary-adrenal and sympathoadrenal systems.ResultsThe RNA-Seq approach was used to perform the comparative adrenal transcriptome profiling in hypertensive ISIAH and normotensive WAG rats. Multiple differentially expressed genes (DEGs) related to different biological processes and metabolic pathways were detected.The discussion of the results helped to prioritize the several DEGs as the promising candidates for further studies of the genetic background underlying the stress-sensitive hypertension development in the ISIAH rats. Two of these were transcription factor genes (Nr4a3 and Ppard), which may be related to the predominant activation of the sympathetic-adrenal medullary axis in ISIAH rats. The other genes are known as associated with hypertension and were defined in the current study as DEGs making the most significant contribution to the inter-strain differences. Four of them (Avpr1a, Hsd11b2, Agt, Ephx2) may provoke the hypertension development, and Mpo may contribute to insulin resistance and inflammation in the ISIAH rats.ConclusionsThe study strongly highlighted the complex nature of the pathogenesis of stress-sensitive hypertension. The data obtained may be useful for identifying the common molecular determinants in different animal models of arterial hypertension, which may be potentially used as therapeutic targets for pharmacological intervention.Electronic supplementary materialThe online version of this article (doi:10.1186/s12864-016-3354-2) contains supplementary material, which is available to authorized users.

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“…In addition to potential repair of the “wet beri-beri” lesions noted above, analyses of the transcriptome in rodent genetic models of hypertension reveal widespread changes in mRNAs encoding components of carbohydrate intermediary metabolism (51–53), including the thiamine-dependent transketolase step in the pentose phosphate pathway.…”

Section: Discussionmentioning

confidence: 99%

Genetic Implication of a Novel Thiamine Transporter in Human Hypertension

Zhang

Huentelman

Rao

et al. 2014

Journal of the American College of Cardiology

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Objectives We coupled two strategies – trait extremes and genome-wide pooling – to discover a novel BP locus that encodes a previously uncharacterized thiamine transporter. Background Hypertension is a heritable trait that remains the most potent and widespread cardiovascular risk factor, though details of its genetic determination are poorly understood. Methods Representative genomic DNA pools were created from male and female subjects in the highest and lowest 5th %iles of BP in a primary care population of >50,000 individuals. The peak associated SNPs were typed in individual DNA samples, as well as twins/siblings phenotyped for cardiovascular and autonomic traits. Biochemical properties of the associated transporter were evaluated in cellular assays. Results After chip hybridization and calculation of relative allele scores, the peak associations were typed in individual samples, revealing association of hypertension, SBP, and DBP to the previously uncharacterized solute carrier SLC35F3. The BP genetic association at SLC35F3 was validated by meta-analysis in an independent sample from the original source population, as well as the ICBP (across North America and Western Europe). Sequence homology to a putative yeast thiamine (vitamin B1) transporter prompted us to express human SLC35F3 in E. coli, which catalyzed [3H]-thiamine uptake. SLC35F3 risk allele (T/T) homozygotes displayed decreased erythrocyte thiamine content on microbiological assay. In twin pairs, the SLC35F3 risk allele predicted heritable cardiovascular traits previously associated with thiamine deficiency, including elevated cardiac stroke volume with decreased vascular resistance, and elevated pressor responses to environmental (cold) stress. Allelic expression imbalance (AEI) confirmed that cis-variation at the human SLC35F3 locus influenced expression of that gene, and the AEI peak coincided with the hypertension peak. Conclusions Novel strategies were coupled to position a new hypertension susceptibility locus, uncovering a previously unsuspected thiamine transporter whose genetic variants predicted several disturbances in cardiac and autonomic function. The results have implications for the pathogenesis and treatment of systemic hypertension.

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Integrated Computational and Experimental Analysis of the Neuroendocrine Transcriptome in Genetic Hypertension Identifies Novel Control Points for the Cardiometabolic Syndrome

Cited by 6 publications

References 44 publications

Mechanisms Responsible for Genetic Hypertension in Schlager BPH/2 Mice

Mechanisms Responsible for Genetic Hypertension in Schlager BPH/2 Mice

Molecular determinants of the adrenal gland functioning related to stress-sensitive hypertension in ISIAH rats

Genetic Implication of a Novel Thiamine Transporter in Human Hypertension

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