ROLE OF ADRENAL PHENYLETHANOLAMINE N-METHYLTRANSFERASE IN GLUCOCORTICOID-MEDIATED FETAL PROGRAMMING OF HYPERTENSION

Program: Abstracts - Orals, Featured Poster Presentations, and Posters
Session: SAT 1-25-Glucocorticoid Actions & HPA Axis
Basic
Saturday, June 15, 2013: 1:45 PM-3:45 PM
Expo Halls ABC (Moscone Center)

Poster Board SAT-9
Sandhya Khurana*1, Phong Nguyen2, Julie Grandbois2, Heather Peltsch2, Amanda Hollingsworth2, Krishnan Venkataraman3 and T.C. Tai1
1Northern Ontario School of Medicine, Sudbury, ON, Canada, 2Laurentian University, Sudbury, ON, Canada, 3Huntington University, Sudbury, ON, Canada
Human health and disease are influenced not only by the genetic make-up of an individual, but also to a great degree by environmental factors. The prenatal environment can be a significant determinant of long-term health outcomes. An adverse fetal milieu such as undernourishment or exposure to environmental insults can have long-term developmental consequences impacting adult health, a phenomenon known as fetal programming. Epidemiological data suggests that conditions in utero can be linked to the development of diseases such as hypertension, diabetes and other pathophysiological conditions in adulthood. Studies suggest that fetal programming of adult diseases is mediated by glucocorticoids (GCs); either endogenous (ex. maternal stress), or exogenous (ex. synthetic GCs administered to aid in the development of the premature babies). Indeed, prenatal exposure to high levels of GCs can predispose the offspring to hypertension. Glucocorticoids regulate catecholamine biosynthesis and are critical for blood pressure homeostasis, with elevated levels leading to hypertension. The purpose of this study was to examine whether prenatal exposure to elevated GC levels influences the development of adult hypertension via alterations in epinephrine synthesis. We investigated the impact of prenatal GC exposure on the post-natal regulation of the gene encoding for phenylethanolamine N-methyltransferase (PNMT), the enzyme involved in the biosynthesis of the catecholamine, epinephrine. PNMT has been linked to hypertension and is elevated in animal models of hypertension. Pregnant Wistar-Kyoto dams were injected with either 100 μg/kg/day of the synthetic glucocorticoid dexamethasone (DEX) or saline in the third trimester of pregnancy. Blood pressure and weights of the offspring were measured (5 to 17 weeks of age), at which point the animals were sacrificed and tissues collected. The results show that systolic, diastolic and mean arterial blood pressures were elevated in male WKY rat offspring born to DEX injected dams (+15%). Adrenal PNMT mRNA was elevated (1.5-fold) in prenatally DEX-exposed rats at 17 weeks.  Additionally, analyses of the transcriptional regulators of the PNMT gene show that prenatal GC exposure increased mRNA levels of Egr-1, AP-2 and GR.  A corresponding increased expression of PNMT protein, along with an elevation of Egr-1, AP-2, and GR protein levels were also observed. Furthermore, GMSA showed increased binding of Egr-1 and GR to the PNMT promoter in DEX exposed animals. These results suggest that prenatal GC exposure increases adrenal PNMT gene expression via altered transcriptional regulation. The study exemplifies the influence of in utero stress on PNMT and thereby epinephrine biosynthesis as a potential mechanism by which elevated prenatal GC levels may program for hypertension later in life.

Nothing to Disclose: SK, PN, JG, HP, AH, KV, TCT

*Please take note of The Endocrine Society's News Embargo Policy at http://www.endo-society.org/endo2013/media.cfm

Sources of Research Support: Supported by an Operating Grant from the Canadian Institutes of Health Research