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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