Abstract 12918: Reduced Splenic and Circulating T Regulatory Cells Contribute to Sympathoexcitation through Central AT1 Receptors in Hypertensive Rats
Background: The adaptive immune system has been suggested to contribute to hypertension and its inflammatory changes. Among the subsets of T lymphocytes, T regulatory cells (Tregs), a key modulator of immune responses by acting as immune suppressants, are reported to prevent angiotensin II (AngII)-induced hypertension and vascular injury. Activation of the brain AngII type 1 receptors (AT1R) elicits sympathoexcitation thereby causing hypertension. The aim of the present study was to determine whether Tregs in various organs are decreased in hypertensive rats compared with normotensive rats, and if so, to examine whether the inhibition of sympathetic activity by central AT1R blockade could increase Tregs thereby attenuates enhanced sympathetic activity in hypertensive rats.
Methods and Results: We used stroke-prone spontaneously hypertensive rats (SHRSP) as hypertensive rats with sympathoexcitation and normotensive Wistar-Kyoto rats (WKY). In both groups, an essential transcription factor of Tregs, Foxp3 mRNA expression levels were greater in the spleen than in other organs (brain, heart, kidney, and small intestine). However, Foxp3 mRNA and protein expression levels in the spleen were significantly lower in SHRSP than in WKY (Foxp3/GAPDH mRNA: 0.47±0.03 vs. 1.02±0.03, n=6 for each, p<0.05, protein: 0.39±0.02 vs. 0.66±0.03, n=6 for each, p<0.05). Flow cytometric analysis revealed that CD4+CD25+Foxp3+ cells (Tregs) in the spleen and blood were significantly lower in SHRSP than in WKY (%Foxp3+ gated on CD4+CD25+ cells in the spleen; 45.4±1.4 vs. 58.1±2.0, n=3 for each, p<0.05, blood; 12.8±1.8 vs. 32.2±4.6, n=3 for each, p<0.05). In SHRSP, intracerebroventricular infusion of AT1R blocker (losartan, 1mg/kg/day for 2 weeks) reduced blood pressure and 24-hour urinary norepinephrine excretion, and upregulated Foxp3 mRNA expression levels in the spleen (0.44±0.04 vs. 0.31±0.02, n=3-4, p<0.05, vs. vehicle-treated SHRSP).
Conclusion: Our findings suggest that reduced splenic and circulating Tregs contribute to the vicious circle formation of sympathoexcitation through central AT1R in SHRSP. Sympathoinhibitory action of central AT1R blockade may break this vicious circle through decreasing the number of Tregs in hypertensive rats.
- © 2012 by American Heart Association, Inc.