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Eric Lazartigues, PhDACE2 Over-expression Regulates AT1, AT2 and MasReceptor Expression and Nitric Oxide Levels in Syn-ACE2 Transgenic Mice
FINANCIAL DISCLOSURE:No relevant financial relationship exists
UNLABELED/UNAPPROVED USES DISCLOSURE:None
Eric Lazartigues1, Yumei Feng1, Yanhui Cai1 and Lisa M. Harrison-Bernard2
Departments of 1Pharmacology & Experimental Therapeutics and 2Physiology, LSU Health Sciences Center, New Orleans
HBPRC 2009
ACE2 Over-expression Regulates AT1, AT2and Mas Receptor Expression and Nitric
Oxide Levels in Syn-ACE2 Transgenic Mice
The local Renin Angiotensin Systems (RAS)
Lavoie, J. L. et al. Endocrinology 2003;144:2179-2183
Central regulation of blood pressure
ACE2 is widely expressed throughout the mouse brain
Doobay et al. Am. J. Physiol. 2007
LaurenTalmanMarc
Doobay
ACE2 in the central regulation of BP and the development of hypertension ?
ACE2
Ang-1-7
Ang-1-9
ACE
Vasodilation
AGT
Ang-I
Ang-II
ACE
AT1a
Renin
Vasoconstriction
Mas
ACE2
Syn-hACE2 transgenic mice over-express ACE2 selectively in the brain
YumeiFeng,
MD-PhD
Do syn-hACE2 mice have reduced hypertension following chronic Ang II
infusion?
-14 -4 0 14 days
Implant probe
Start BP recording
Autonomic and baroreflexfunction
Osmotic pump: (600ng/kg/min)Ang II Ang II+D-ala7 Ang 1-7D-ala7 Ang 1-7Saline
Yumei Feng, MD-PhD
Huijing Xia,PhD
******
******
Ang-(1-7) receptor blockade reverses theanti-hypertensive effect of ACE2
Grobe, J. L. et al. Physiology 23: 187-193 2008
Brain RAS: a working model
Increases sympathetic outflow, BP, water intake, salt appetite, AVP release. Decreases baroreflex gain and vagal tone.
Increases NO release. Decreases sympathetic outflow and BP?
Decreases sympathetic outflow, BP. Increases NO release, baroreflexgain and vagal tone.
Angiotensin receptors expression in the brainstem
Yumei Feng, MD-PhD
Yanhui Cai, MSc
Angiotensin receptors expression in Neuro2A cells
NO levels in the cerebrospinal fluid
Methodology:
• Pre-calibrated NO probe inserted in the
lateral ventricle of anesthetized mice
• Amperometric detection of NO current (Apollo
4000, WPI Inc.)
Standard curve
Yumei Feng, MD-PhD
Summary
ACE2 overexpression
Ang-1-7 Ang-II
AT1a
↑ BP
ACE2
Increase in NOS expression
Down-regulationof AT1 receptors
Up-regulationof Mas receptors
Reduction of sympathetic tone and BP levelRestoration of parasympathetic tone
and baroreflex sensitivity
Mas
↓ BP
Up-regulationof AT2 receptors
Increase in NO release
Conclusion
• Brain ACE2 can play a pivotal role in the central regulation of blood pressure and
the prevention of neurogenic hypertension
• Development of new therapeuticsand better use of existing therapeutics
Acknowledgements
Transgenic Animal Facilityand Sigmund’s Lab(University of Iowa)Dr. Curt D. SigmundCarmen Halabi
Davisson’s Lab(University of Iowa)Dr. Robin L. DavissonMarc F. DoobayLauren S. Talman
Lazartigues’ Lab(LSUHSC)Dr. Xinping YueDr. Yumei FengDr. Huijing XiaYanhui CaiPeter Hickman
FundingNIH/NINDSNIH/NCRRNIH/NHLBI
Dr. Ferrario’s Group(Wake Forest Univ.)
Coffman Lab(Duke University)Dr. Tom CoffmanDr. Susan GurleyKamie Snow
GeneLogic Inc.
Navar’s Lab(Tulane University)Dr. LG NavarDale Seth
ACE2 over-expression attenuates the developmentof Ang II-induced hypertension in syn-ACE2 mice
******
NOS expression in the brainstem
Yumei Feng, MD-PhD
Yanhui Cai, MSc
hACE2 over-expression decreases AT1 receptor expression in the SFO
Feng et al. Circ. Res. 2008, 102:729-736