Introduction to ROS in the Cardiovascular System John F. Keaney, Jr., M.D. UMass Medical School...
Transcript of Introduction to ROS in the Cardiovascular System John F. Keaney, Jr., M.D. UMass Medical School...
![Page 1: Introduction to ROS in the Cardiovascular System John F. Keaney, Jr., M.D. UMass Medical School Worcester, MA.](https://reader036.fdocuments.in/reader036/viewer/2022062518/56649ec95503460f94bd69c7/html5/thumbnails/1.jpg)
Introduction to ROS inthe Cardiovascular System
John F. Keaney, Jr., M.D.UMass Medical School
Worcester, MA
![Page 2: Introduction to ROS in the Cardiovascular System John F. Keaney, Jr., M.D. UMass Medical School Worcester, MA.](https://reader036.fdocuments.in/reader036/viewer/2022062518/56649ec95503460f94bd69c7/html5/thumbnails/2.jpg)
Role of ROS in CV Disease: Antiquated
NEJM, 1997
![Page 3: Introduction to ROS in the Cardiovascular System John F. Keaney, Jr., M.D. UMass Medical School Worcester, MA.](https://reader036.fdocuments.in/reader036/viewer/2022062518/56649ec95503460f94bd69c7/html5/thumbnails/3.jpg)
Homeostasis
Endogenous Sources
MitochondriaPeroxisomesLipoxygenasesNADPH OxidasesCytochrome P450
AntioxidantDefenses
Enzymatic Systems: CAT, SOD, GPXNon-enzymatic systems: Glutathione Vitamins
Impaired PhysiologicFunction
Impaired PhysiologicFunction
NormalDecreased Repair
Decreased Adaptive Responses
Random Oxidation
Specific SignalPathways
Vascular and MyocardialDisease
Vascular and MyocardialDisease
ROS/RNS
Adapted from Finkel and Holbrook, 2007
![Page 4: Introduction to ROS in the Cardiovascular System John F. Keaney, Jr., M.D. UMass Medical School Worcester, MA.](https://reader036.fdocuments.in/reader036/viewer/2022062518/56649ec95503460f94bd69c7/html5/thumbnails/4.jpg)
NADPH Oxidases
Neutrophil “Burst” Oxidase NADPH Oxidase (Nox) Enzyme Family
Bedard and Krause, Physiol. Rev. 2007;87
![Page 5: Introduction to ROS in the Cardiovascular System John F. Keaney, Jr., M.D. UMass Medical School Worcester, MA.](https://reader036.fdocuments.in/reader036/viewer/2022062518/56649ec95503460f94bd69c7/html5/thumbnails/5.jpg)
Contemporary ROS and CV System:Major Areas of Influence
Cardiac FunctionHypertrophy
AtherosclerosisHypertension
AngiogenesisVascular Repair
![Page 6: Introduction to ROS in the Cardiovascular System John F. Keaney, Jr., M.D. UMass Medical School Worcester, MA.](https://reader036.fdocuments.in/reader036/viewer/2022062518/56649ec95503460f94bd69c7/html5/thumbnails/6.jpg)
Contemporary ROS and CV System:Major Areas of Influence
Cardiac FunctionHypertrophy
AtherosclerosisHypertension
AngiogenesisVascular Repair
![Page 7: Introduction to ROS in the Cardiovascular System John F. Keaney, Jr., M.D. UMass Medical School Worcester, MA.](https://reader036.fdocuments.in/reader036/viewer/2022062518/56649ec95503460f94bd69c7/html5/thumbnails/7.jpg)
NADPH Oxidase (Nox) Enzyme Family
Bedard and Krause, Physiol. Rev. 2007;87
![Page 8: Introduction to ROS in the Cardiovascular System John F. Keaney, Jr., M.D. UMass Medical School Worcester, MA.](https://reader036.fdocuments.in/reader036/viewer/2022062518/56649ec95503460f94bd69c7/html5/thumbnails/8.jpg)
Nox2 Influences Cardiac RemodelingAfter Myocardial Infarction
Hypertension. 2008 Feb;51(2):319-25
• Less pathologic heart remodeling
• Reduced change to the fetal gene program
• Less apoptosis
![Page 9: Introduction to ROS in the Cardiovascular System John F. Keaney, Jr., M.D. UMass Medical School Worcester, MA.](https://reader036.fdocuments.in/reader036/viewer/2022062518/56649ec95503460f94bd69c7/html5/thumbnails/9.jpg)
NADPH Oxidase (Nox) Enzyme Family
Bedard and Krause, Physiol. Rev. 2007;87
![Page 10: Introduction to ROS in the Cardiovascular System John F. Keaney, Jr., M.D. UMass Medical School Worcester, MA.](https://reader036.fdocuments.in/reader036/viewer/2022062518/56649ec95503460f94bd69c7/html5/thumbnails/10.jpg)
Trans Aortic Constriction Model
AorticSuture
WT TAC
![Page 11: Introduction to ROS in the Cardiovascular System John F. Keaney, Jr., M.D. UMass Medical School Worcester, MA.](https://reader036.fdocuments.in/reader036/viewer/2022062518/56649ec95503460f94bd69c7/html5/thumbnails/11.jpg)
Cardiac Nox4 is Deleterious in Pressure Overload
Kuroda J et al. PNAS 2010;107:15565-15570
• Less pathologic hypertrophy
• Improved function (ejection fraction)
• Less apoptosis
![Page 12: Introduction to ROS in the Cardiovascular System John F. Keaney, Jr., M.D. UMass Medical School Worcester, MA.](https://reader036.fdocuments.in/reader036/viewer/2022062518/56649ec95503460f94bd69c7/html5/thumbnails/12.jpg)
Nox4 Impacts Multiple ROS Sources
Kuroda J et al. PNAS 2010;107:15565-15570
![Page 13: Introduction to ROS in the Cardiovascular System John F. Keaney, Jr., M.D. UMass Medical School Worcester, MA.](https://reader036.fdocuments.in/reader036/viewer/2022062518/56649ec95503460f94bd69c7/html5/thumbnails/13.jpg)
Interaction of ROS Sources
Cave et. al. Antioxid. Redox Signal. 8, 691–728
![Page 14: Introduction to ROS in the Cardiovascular System John F. Keaney, Jr., M.D. UMass Medical School Worcester, MA.](https://reader036.fdocuments.in/reader036/viewer/2022062518/56649ec95503460f94bd69c7/html5/thumbnails/14.jpg)
Contemporary ROS and CV System:Major Areas of Influence
Cardiac FunctionHypertrophy
AtherosclerosisHypertension
AngiogenesisVascular Repair
![Page 15: Introduction to ROS in the Cardiovascular System John F. Keaney, Jr., M.D. UMass Medical School Worcester, MA.](https://reader036.fdocuments.in/reader036/viewer/2022062518/56649ec95503460f94bd69c7/html5/thumbnails/15.jpg)
NADPH Oxidase (Nox) Enzyme Family
Bedard and Krause, Physiol. Rev. 2007;87
![Page 16: Introduction to ROS in the Cardiovascular System John F. Keaney, Jr., M.D. UMass Medical School Worcester, MA.](https://reader036.fdocuments.in/reader036/viewer/2022062518/56649ec95503460f94bd69c7/html5/thumbnails/16.jpg)
NADPH Oxidase Activity and Atherosclerosis
• ApoE(-/-) mice with or without p47phox
• Animals on chow followed for 30 weeks
• ROS production measured by DHE staining
• Atherosclerosis determined by aortic lipid content
Barry-Lane et al. J. Clin. Invest. 2001;108:1513
0
50
100
150
RO
SF
lux
(+/+) (-/-)
p47Phox Status
0
2
4
6
Les
ion
(mm
2)
(+/+) (-/-)
p47Phox Status
*
*
*P<0.05
![Page 17: Introduction to ROS in the Cardiovascular System John F. Keaney, Jr., M.D. UMass Medical School Worcester, MA.](https://reader036.fdocuments.in/reader036/viewer/2022062518/56649ec95503460f94bd69c7/html5/thumbnails/17.jpg)
What about hypertension?
![Page 18: Introduction to ROS in the Cardiovascular System John F. Keaney, Jr., M.D. UMass Medical School Worcester, MA.](https://reader036.fdocuments.in/reader036/viewer/2022062518/56649ec95503460f94bd69c7/html5/thumbnails/18.jpg)
Renin-Angiotensin System
![Page 19: Introduction to ROS in the Cardiovascular System John F. Keaney, Jr., M.D. UMass Medical School Worcester, MA.](https://reader036.fdocuments.in/reader036/viewer/2022062518/56649ec95503460f94bd69c7/html5/thumbnails/19.jpg)
NADPH Oxidase (Nox) Enzyme Family
Bedard and Krause, Physiol. Rev. 2007;87
![Page 20: Introduction to ROS in the Cardiovascular System John F. Keaney, Jr., M.D. UMass Medical School Worcester, MA.](https://reader036.fdocuments.in/reader036/viewer/2022062518/56649ec95503460f94bd69c7/html5/thumbnails/20.jpg)
Nox2 and Hypertension
Landmesser, U. et al. Hypertension 2002;40:511-515
• Less ROS produced from blood vessels
• Less rise in blood pressure
• Less vascular hypertrophy
![Page 21: Introduction to ROS in the Cardiovascular System John F. Keaney, Jr., M.D. UMass Medical School Worcester, MA.](https://reader036.fdocuments.in/reader036/viewer/2022062518/56649ec95503460f94bd69c7/html5/thumbnails/21.jpg)
Not all ROS sources are equal!
![Page 22: Introduction to ROS in the Cardiovascular System John F. Keaney, Jr., M.D. UMass Medical School Worcester, MA.](https://reader036.fdocuments.in/reader036/viewer/2022062518/56649ec95503460f94bd69c7/html5/thumbnails/22.jpg)
NADPH Oxidase (Nox) Enzyme Family
Bedard and Krause, Physiol. Rev. 2007;87
![Page 23: Introduction to ROS in the Cardiovascular System John F. Keaney, Jr., M.D. UMass Medical School Worcester, MA.](https://reader036.fdocuments.in/reader036/viewer/2022062518/56649ec95503460f94bd69c7/html5/thumbnails/23.jpg)
BP and Hypertrophy are Distinct
Matsuno, K. et al. Circulation 2005;112:2677-2685
Ang II Infusion
![Page 24: Introduction to ROS in the Cardiovascular System John F. Keaney, Jr., M.D. UMass Medical School Worcester, MA.](https://reader036.fdocuments.in/reader036/viewer/2022062518/56649ec95503460f94bd69c7/html5/thumbnails/24.jpg)
Contemporary ROS and CV System:Major Areas of Influence
Cardiac FunctionHypertrophy
AtherosclerosisHypertension
AngiogenesisVascular Repair
![Page 25: Introduction to ROS in the Cardiovascular System John F. Keaney, Jr., M.D. UMass Medical School Worcester, MA.](https://reader036.fdocuments.in/reader036/viewer/2022062518/56649ec95503460f94bd69c7/html5/thumbnails/25.jpg)
NADPH Oxidase (Nox) Enzyme Family
Bedard and Krause, Physiol. Rev. 2007;87
![Page 26: Introduction to ROS in the Cardiovascular System John F. Keaney, Jr., M.D. UMass Medical School Worcester, MA.](https://reader036.fdocuments.in/reader036/viewer/2022062518/56649ec95503460f94bd69c7/html5/thumbnails/26.jpg)
Bone Marrow Nox2 is Important for Ischemia-Induced Angiogenesis
Urao, N. et al. Circ Res 2008;103:212-220
• Lack of Nox2 impairs ischemia-induced angiogenesis
• This effect is most prominent in bone marrow
![Page 27: Introduction to ROS in the Cardiovascular System John F. Keaney, Jr., M.D. UMass Medical School Worcester, MA.](https://reader036.fdocuments.in/reader036/viewer/2022062518/56649ec95503460f94bd69c7/html5/thumbnails/27.jpg)
Chen et al., PNAS 2004;101:13014-13019
Nox2 Modifies Arterial Injury
IEL
Wild-type, 28d
IEL
Nox2-/- , 28d
Intima:Media
0
0.2
0.4
0.6
0.8
1
1.2
1.4
1.6
39%P=0.036
WT Nox2-/-
![Page 28: Introduction to ROS in the Cardiovascular System John F. Keaney, Jr., M.D. UMass Medical School Worcester, MA.](https://reader036.fdocuments.in/reader036/viewer/2022062518/56649ec95503460f94bd69c7/html5/thumbnails/28.jpg)
How about other ROS Sources?
![Page 29: Introduction to ROS in the Cardiovascular System John F. Keaney, Jr., M.D. UMass Medical School Worcester, MA.](https://reader036.fdocuments.in/reader036/viewer/2022062518/56649ec95503460f94bd69c7/html5/thumbnails/29.jpg)
Mitochondrial ROS are Important for Hypoxic Responses
Guzy et al. , Cell Metabolism, 2005
b
b b
![Page 30: Introduction to ROS in the Cardiovascular System John F. Keaney, Jr., M.D. UMass Medical School Worcester, MA.](https://reader036.fdocuments.in/reader036/viewer/2022062518/56649ec95503460f94bd69c7/html5/thumbnails/30.jpg)
Take Home Points
• ROS are ubiquitous, and serve as cellular messengers
• ROS responses are generally linked to injury and repair responses
• ROS sources and the regulation of these sources has, thus far, proven the most fruitful means of impacting disease
• NADPH oxidases are one important source of ROS in the cardiovascular system
![Page 31: Introduction to ROS in the Cardiovascular System John F. Keaney, Jr., M.D. UMass Medical School Worcester, MA.](https://reader036.fdocuments.in/reader036/viewer/2022062518/56649ec95503460f94bd69c7/html5/thumbnails/31.jpg)
What we do not yet know
• Which source(s) of ROS are specific for certain pathologic disorders
• How do the different source(s) of ROS relate to each other
• What are the “normal” mechanisms for specificity of ROS species
• Which ROS/RNS are most important in specific disease(s)