Cardiac phenylethanolamine N-methyltransferase: localization and regulation of gene expression in the spontaneously hypertensive rat

Peltsch, Heather; Khurana, Sandhya; Byrne, Collin J.; Nguyen, Phong; Khaper, Neelam; Kumar, Aseem; Tai, T.C.

doi:10.1139/cjpp-2015-0303

Cited by 8 publications

(6 citation statements)

References 80 publications

(109 reference statements)

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“…2,3 Though the role of hPNMT in the human central nervous system (CNS) has yet to be fully elucidated, epinephrine has been associated with a number of CNS processes such as cardiovascular homeostasis, adrenergic receptor activation, learning and memory, and regulation of the circadian cycle. 1 In addition, studies suggest hPNMT may play a role in several human disease states including hypertension, 4 myocardial infarction, 5 Alzheimer's disease, 6 and Parkinson's disease. 7,8 Recently, density functional theory (DFT) 9 and quantum mechanics/molecular mechanics (QM/MM) 10 methods have been used to investigate the hPNMT reaction mechanism.…”

mentioning

confidence: 99%

Kinetic Isotope Effects and Transition State Structure for Human Phenylethanolamine N-Methyltransferase

Stratton

Poulin

et al. 2016

ACS Chem. Biol.

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Phenylethanolamine N-methyltransferase (PNMT) catalyzes the S-adenosyl-l-methionine (SAM)-dependent conversion of norepinephrine to epinephrine. Epinephrine has been associated with critical processes in humans including the control of respiration and blood pressure. Additionally, PNMT activity has been suggested to play a role in hypertension and Alzheimer’s disease. In the current study, labeled SAM substrates were used to measure primary methyl-14C and 36S and secondary methyl-3H, 5′-3H, and 5′-14C intrinsic kinetic isotope effects for human PNMT. The transition state of human PNMT was modeled by matching kinetic isotope effects predicted via quantum chemical calculations to intrinsic values. The model provides information on the geometry and electrostatics of the human PNMT transition state structure and indicates that human PNMT catalyzes the formation of epinephrine through an early SN2 transition state in which methyl transfer is rate-limiting.

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mentioning

confidence: 99%

Kinetic Isotope Effects and Transition State Structure for Human Phenylethanolamine N-Methyltransferase

Stratton

Poulin

et al. 2016

ACS Chem. Biol.

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“…Recent evidence supports that overexpression of the PNMT gene in adrenal glands, heart and brainstem of SHRs is caused by altered transcriptional regulation, and contributes to their hypertensive phenotype [11,23,24]. Studies from our lab have also previously demonstrated that the expression of adrenal PNMT is elevated when offspring are exposed to high doses of DEX prenatally, caused by altered transcriptional mechanisms [25].…”

Section: Introductionmentioning

confidence: 86%

Fetal programming of adrenal PNMT and hypertension by glucocorticoids in WKY rats is dose and sex-dependent

et al. 2019

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Biochemical changes in utero may alter normal fetal development, resulting in disease later in life, a phenomenon known as fetal programming. Recent epidemiological studies link fetal programming to negative health outcomes, such as low birth weight and hypertension in adulthood. Here, we used a WKY rat model and studied the molecular changes triggered by prenatal glucocorticoid (GC) exposure on the development of hypertension, and on the regulation of phenylethanolamine N-methyl transferase (PNMT), the enzyme responsible for biosynthesis of epinephrine, and a candidate gene linked to hypertension. Clinically, high doses of the synthetic GC dexamethasone (DEX) are used to treat infant respiratory distress syndrome. Elevated maternal GCs have been correlated with fetal programming of hypertension. The aim of this study was to determine if lower doses of DEX would not lead to detrimental fetal programming effects such as hypertension. Our data suggests that prenatal stress programs for increased expression of PNMT and altered regulation of PNMT in males and females. Importantly, we identified that DEX mediated programming was more apparent in the male rats, and the lower dose 10μg/kg/day of DEX did not lead to changes in blood pressure (BP) in female rats suggesting that this dose is below the threshold for programming of hypertension. Furthermore, sex-specific differences were observed in regards to programming mechanisms that may account for hypertension in males.

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“…Доказана связь между низкими показателями Другие проблемы эндокринологии массы тела при рождении и программированием развития гипертонии с нарушениями развития почек и регуляции ренин-ангиотензин-альдостероновой системы [16], изменением структуры и функции сосудов [17], а также изменением активности гипоталамогипофизарно-надпочечниковой [18] и симпатоадреналовой систем [19,20]. Результаты недавних исследований демонстрируют, что сверхэкспрессия гена фенилэтаноламин-N-метилтрансферазы (PNMT) в надпочечниках, сердце и стволе мозга вызывается изменением регуляции транскрипции и вносит вклад в их гипертензивный фенотип [21]. Ранее были опубликованы данные, свидетельствующие о том, что экспрессия надпочечникового PNMT повышается, когда потомство подвергается пренатальному воздействию высоких доз, что вызвано измененными механизмами транскрипции [22].…”

Section: антенатальная глюкокортикостероидная терапия и риск сердечно...unclassified

Antenatal glucocorticosteroids treatment: mechanisms of child healths programming

Шайтарова

Суплотова

2022

Medicinskij sovet

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Synthetic glucocorticoids are widely used in pregnancies at risk of preterm delivery and in pregnant women at risk of having a child with severe 21-hydroxylase deficiency. The positive effects of reducing mortality in preterm and virilisation in girls with congenital adrenal hyperplasia are now unquestionable. The adrenogenital syndrome responding to 21-hydroxylase deficiency is a common, potential fatal disease. Its incidence calculated on the basis of neonatal screening data makes 1 case for 14000 live newborns among the worldwide population, 1 for 9638 – In Russia. DEX passes through the placenta and decreases fetal ACTH production thereby suppressing the fetal production of androgens. The prenatal treatment does not preclude from a life-long treatment in future and it is not prevention of a salt-losing syndrome at the postnatal period, and dexamethasone safety in relation to cognitive development of children prenatally treated with dexamethasone is still up for debate. Adding to the concern is the fact that the doses of DEX that the fetus is exposed to are estimated to be 60 times the normal fetal cortisol level. The glucocorticoid and the mineralocorticoid receptors are highly expressed in the hippocampus, amygdala, and prefrontal cortex. These areas, important for executive functioning, emotional regulation, and memory, are vulnerable to high doses of GCs. Most experimental data from animal have shown that prenatal exposure to synthetic glucocorticoids programs the foetal HPA and may lead to altered susceptibility to metabolic and cardiovascular disease i.e. metabolic syndrome, high blood pressure. Prenatal glucocorticoid exposure also leads to modification of HPAassociated behaviours and cognition.

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Cardiac phenylethanolamine N-methyltransferase: localization and regulation of gene expression in the spontaneously hypertensive rat

Cited by 8 publications

References 80 publications

Kinetic Isotope Effects and Transition State Structure for Human Phenylethanolamine N-Methyltransferase

Kinetic Isotope Effects and Transition State Structure for Human Phenylethanolamine N-Methyltransferase

Fetal programming of adrenal PNMT and hypertension by glucocorticoids in WKY rats is dose and sex-dependent

Antenatal glucocorticosteroids treatment: mechanisms of child healths programming

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