CaMKII和心力衰竭(英文)-课件,幻灯共23页
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CaMKII和心力衰竭(英文)-课件，幻灯
11、用道德的示范来造就一个人，显然比用法律来约束他更有价值。—— 希腊
12、法律是无私的，对谁都一视同仁。在每件事上，她都不徇私情。—— 托马斯
13、公正的法律限制不了好的自由，因为好人不会去做法律不允许的事 情。——弗劳德
14、法律是为了保护无辜而制定的。——爱略特 15、像房子一样，法律和法律都是相互依存的。——伯克
40
n = 11
n = 13
20
WT 40
CaMKII KO NS
30
20
n=21
n=17
WT CaMKII KO
WT HF CaMKII KO HF
NS
10
n=21
n=17
EF
FS
LV ejection fraction and fractional shortening (%)
Unchanged CaMKIIg expression and reduced CaMKII activity in CaMKIId KO HF
CaMKII inhibition protects against structural heart disease
J Clin Invest. 2009, 119(5): 1230–1240
Summary
• CaMKII plays an important role in the development of cardiac hypertrophy and failure by activation of hypertrophic gene grogram and increasing SR Ca2+ leak and myocyte apoptosis.
Circulation Research. 2004;94:e61.
CaMKII-overexpression causes dysfunction of E-C coupling and HF
Mechanisms for CaMKII-induced cardiac hypertrophy and failure
NFAT, MEF2, GATA4
Fetal gene activation and cardiac remodeling
Histone Deacetylase MEF:myocyte enhancer factor
Ca2+
CaMK:Protein cFra bibliotekinasi Ca/Calmodulina-dipendente (fosfatasi) Nuclear Factor of Activated T cells
0.5 WT-HF (n=11) CaMKII KO-HF (n=14)
0.4
0.3
0.2
0.1
Ca2+ leak (F/F ) 0
0.4
0.6
0.8
1.0
SR Content (F/F ) 0
Sarcomere shortening
62 KD 54 KD 7 KD 42 KD
CaMKIId WT HF KO HF
g d CaMKII
p-PLB (Thr17)
a-Actinin
CaMKII inhibition in HF reduces SR Ca2+ leak but slows Ca2+ transient decay and relaxation
(sTAB) in CaMKIIδ KO mice
WT
CaMKII KO
WT HF
CaMKII KO HF
LV ejection fraction (%)
LV fractional shortening (%)
120 100
80 60 40 20
p < 0.05
n = 11
n = 13
80
p < 0.05 60
• CaMKII-inhibition is a potential clinical therapeutic target.
What is the long term effect of CaMKII
inhibition on cardiac function ?
A pressure-overload HF model has been generated by severe thoracic aortic banding
Cardiac CaMKII activation
Inactive
active
Ca2+-independent
Ca2+/CaM
Phosphatase
Phosphate
active
CaM-band
active
CaM-trapped
Role of Cardiac CaMKII
CaMKII and E-C Coupling
CaMKII and Heart Failure
Yanggan Wang, MD, PhD
INTRODUCTION
5 million patients with Heart failure in US. 0.5 million new HF patients and 0.25 million deaths annually.
Neural hormonal signals
Biomechanical stress
Guanylyl Adenylyl Cyclase cyclase
Receptors
Gαq
TRPC
Ca2+
SAC
Stretch sensor
PKC
PKA
MAPK Calcineurin CaMKII
Transcription factors
CaMKIId KO normalizes the expression of Ca2+ regulatory proteins and reduces RyR2 phosphorylation and Ca2+ leak after TAB
J Clin Invest. 2009, 119(5): 1230–1240
The precise mechanisms underlying the contractile and electrical abnormalities of hypertrophy and HF remains elusive.
Ineffective therapies.
Natriuretic peptide
11、用道德的示范来造就一个人，显然比用法律来约束他更有价值。—— 希腊
12、法律是无私的，对谁都一视同仁。在每件事上，她都不徇私情。—— 托马斯
13、公正的法律限制不了好的自由，因为好人不会去做法律不允许的事 情。——弗劳德
14、法律是为了保护无辜而制定的。——爱略特 15、像房子一样，法律和法律都是相互依存的。——伯克
40
n = 11
n = 13
20
WT 40
CaMKII KO NS
30
20
n=21
n=17
WT CaMKII KO
WT HF CaMKII KO HF
NS
10
n=21
n=17
EF
FS
LV ejection fraction and fractional shortening (%)
Unchanged CaMKIIg expression and reduced CaMKII activity in CaMKIId KO HF
CaMKII inhibition protects against structural heart disease
J Clin Invest. 2009, 119(5): 1230–1240
Summary
• CaMKII plays an important role in the development of cardiac hypertrophy and failure by activation of hypertrophic gene grogram and increasing SR Ca2+ leak and myocyte apoptosis.
Circulation Research. 2004;94:e61.
CaMKII-overexpression causes dysfunction of E-C coupling and HF
Mechanisms for CaMKII-induced cardiac hypertrophy and failure
NFAT, MEF2, GATA4
Fetal gene activation and cardiac remodeling
Histone Deacetylase MEF:myocyte enhancer factor
Ca2+
CaMK:Protein cFra bibliotekinasi Ca/Calmodulina-dipendente (fosfatasi) Nuclear Factor of Activated T cells
0.5 WT-HF (n=11) CaMKII KO-HF (n=14)
0.4
0.3
0.2
0.1
Ca2+ leak (F/F ) 0
0.4
0.6
0.8
1.0
SR Content (F/F ) 0
Sarcomere shortening
62 KD 54 KD 7 KD 42 KD
CaMKIId WT HF KO HF
g d CaMKII
p-PLB (Thr17)
a-Actinin
CaMKII inhibition in HF reduces SR Ca2+ leak but slows Ca2+ transient decay and relaxation
(sTAB) in CaMKIIδ KO mice
WT
CaMKII KO
WT HF
CaMKII KO HF
LV ejection fraction (%)
LV fractional shortening (%)
120 100
80 60 40 20
p < 0.05
n = 11
n = 13
80
p < 0.05 60
• CaMKII-inhibition is a potential clinical therapeutic target.
What is the long term effect of CaMKII
inhibition on cardiac function ?
A pressure-overload HF model has been generated by severe thoracic aortic banding
Cardiac CaMKII activation
Inactive
active
Ca2+-independent
Ca2+/CaM
Phosphatase
Phosphate
active
CaM-band
active
CaM-trapped
Role of Cardiac CaMKII
CaMKII and E-C Coupling
CaMKII and Heart Failure
Yanggan Wang, MD, PhD
INTRODUCTION
5 million patients with Heart failure in US. 0.5 million new HF patients and 0.25 million deaths annually.
Neural hormonal signals
Biomechanical stress
Guanylyl Adenylyl Cyclase cyclase
Receptors
Gαq
TRPC
Ca2+
SAC
Stretch sensor
PKC
PKA
MAPK Calcineurin CaMKII
Transcription factors
CaMKIId KO normalizes the expression of Ca2+ regulatory proteins and reduces RyR2 phosphorylation and Ca2+ leak after TAB
J Clin Invest. 2009, 119(5): 1230–1240
The precise mechanisms underlying the contractile and electrical abnormalities of hypertrophy and HF remains elusive.
Ineffective therapies.
Natriuretic peptide