1. Ricardo A. Pena, M.D.

2. Impact of ACE2 Deficiency and Oxidative Stress in Cerebrovascular Dysfunction with Aging
Ricardo Pena-Silva 1,3; Yi Chu2; Jordan Miller2; Ian Mitchell2; Josef Penninger 4; Frank Faraci1,2; Donald Heistad1,2
Departments of Pharmacology1, Internal medicine2, University of Iowa, College of Medicine, Iowa City, IA; Medical School, Universidad de los Andes3, Bogota, Colombia; Institute for Molecular Biotechnology of the Austrian Academy of Sciences4, Vienna, Austria.
Disclosures: None

3. Blood supply to an area of heart muscle is blocked,
“Heart Attack”
Blood supply to an area of heart muscle is blocked,
usually by a clot in a coronary artery
If not treated within a few hours, the affected heart muscle will die

4. Stroke “Brain Attack”
A stroke is the sudden death of brain cells in a localized area due to inadequate blood flow.
Without blood to supply oxygen and nutrients and to remove waste products, brain cells quickly begin to die
Ischemic stroke
Blood clot blocks an artery in the brain
Hemorrhagic stroke
Blood vessel in the brain leaks or bursts (more deadly)

5. Effects of Angiotensin II in Blood Vessels
ACE 2
Protects blood vessels
Vasodilation
Decreases free radicals
Angiotensin (1-7) axis
Classical view
Angiotensin II
Vasoconstriction
Free radicals
Vascular Dysfunction
“Sick” blood vessel
Hypothesis:
ACE 2 deficiency is associated with impaired vascular function in cerebral arteries

6. Assessment of Vascular function
Vasoconstrictor
KCL
Thromboxane A2 analog (U46619)
Vasodilator
Acetylcholine
(Ach)
Sodium Nitroprusside (SNP)
ACE2 KO / WT
Adult (12 Mo)
Old (21 Mo)
Pena RA
JCBFM 1998, (18), 570

7. Effects of ACE2 deficiency on vascular function Adult mice
WT + Tempol WT
ACE2 KO + Tempol *
ACE2 KO
mm Hg
Pena RA.
*=p<0.01

8. Statistical problems Best way to analyze the results
One way Anova vs 2 way anova
Repeated measures

9. Angiotensin II, ACE2 and Aging
ACE2 is the receptor for the SARS coronavirus, and prevalence of SARS infection was lower in older individuals.
(Liang W et al. Emerg Infect Dis. 2004)
Aging decreases ACE2 expression in rat lungs
(Xudong X, et al. Life Sciences. 2006)

10. Hypothesis
ACE 2 deficiency is associated with impaired vascular function in cerebral arteries
Aging will aggravate the effects of ACE 2 deficiency in cerebral vascular function

11. Effects of Aging on vascular function
Maximal Relaxation to ACh
Systolic Blood Pressure #
# = p<0.05
Pena RA.

12. Effects of ACE2 deficiency on vascular function Old miceKO # # WT * * * *
WT + Tempol
KO + Tempol
n=6 mice
Pena RA.

13. Aging increases NADPH oxidase expression in cerebral arteries
Enzymes that produce free radicals
Increased in old mice
Pena RA.

14. Endothelial dysfunction
Summary Model
ACE2
Angiotensin II
Angiotensin 1-7
Aging impairs vascular function in both ACE2 KO and WT mice
ACE2 deficiency impairs cerebrovascular function and aggravates dysfunction with aging
Oxidative stress plays an important role in vascular dysfunction in ACE2 KO mice and during aging
AT1
NAD(p)H Oxidase
Aging
Oxidative stress
Tempol
Endothelial dysfunction

15. Acknowledgements Funding Predoctoral Fellowship AHA
University of Iowa Members: Heistad’s Lab Frank Faraci’s Lab Collaborators: Josef Penninger (IMBA, Austria) Michael Bader / Natasha Alenina (MDC) Robson Santos (UFMG) Jordan Miller, (Mayo Clinic)
Funding
Predoctoral Fellowship AHA
G - 10PRE
Faculty Development Program
Universidad de los Andes
Fulbright Commission in Colombia and US 15