Hypertension in transgenic mice with brain-selective overexpression of the alpha(2B)-adrenoceptor.
BACKGROUND
Previous studies have shown that the presynaptic alpha(2B)-adrenoceptor subtype in the central nervous system has a sympathoexcitatory function and its activation leads to a hyperadrenergic hypertensive state. The purpose of this project was to develop a novel hyperadrenergic model, a transgenic (TG) mouse model with brain-selective overexpression of the alpha(2B)-adrenergic receptor (alpha(2B)-AR).


METHODS
We used Southern blot analysis to confirm transgene, real-time PCR to assess gene expression, western Blot analysis and immunohistology to assess protein expression and localization in brain areas. Indirect blood pressure (BP) and heart rate were recorded.


RESULTS
In TG mice there was a 1.8-fold increase in alpha(2B)-AR protein expression compared to wild-type (WT) mice. Immunostaining of brain sections revealed that concentration of alpha(2B)-AR was much more pronounced in TG than in WT mice. Systolic BP at 8 weeks of age was significantly elevated in TG 130 +/- 6 mm Hg, compared with WT control nontransgenic littermates of the same age 107 +/- 7 mm Hg, (P < 0.05), indicating that the TG mice had indeed developed hypertension.


CONCLUSIONS
We have therefore documented that overexpression of the alpha(2B)-AR gene leads to increased production of alpha(2B)-AR protein in brain regions known to regulate central sympathetic outflow, thus resulting in sustained BP elevation. This is a unique model of experimental hypertension driven purely by overexpression of the alpha(2B)-AR that would result in an overactive sympathetic system and would be suitable for testing the pharmacologic properties of potential therapeutic agents.
Kintsurashvili
Ekaterina
E
Hypertension and Atherosclerosis Section, Department of Medicine, Boston University School of Medicine, Boston, Massachusetts, USA.
Shenouda
Sherene
S
Ona
Deborah
D
Ona
Leonardo
L
Ahmad
Saad
S
Ravid
Katya
K
Gavras
Irene
I
Gavras
Haralambos
H
D000818:Animals; D001794:Blood Pressure / Q000502:physiology; D015139:Blotting, Southern; D015153:Blotting, Western; D001921:Brain / Q000378:metabolism; D004247:DNA / Q000235:genetics*; D004195:Disease Models, Animal; D005500:Follow-Up Studies; D015870:Gene Expression; D020022:Genetic Predisposition to Disease; D006973:Hypertension / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology; D007150:Immunohistochemistry; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D018341:Receptors, Adrenergic, alpha-2 / Q000096:biosynthesis / Q000235:genetics*; D020133:Reverse Transcriptase Polymerase Chain Reaction
C547772:Adra2b protein, mouse; D018341:Receptors, Adrenergic, alpha-2; D004247:DNA