Transcript concentric pattern of ventricular hypertrophy.

Nitric Oxide & Heart Failure
Focus on Cardiomyocyte
Contractility, Apoptosis and
Hypertrophy
03级基础医学
周洲 李兴哲 陆峥飞 肖楠 董婧 袁方
Background
 Biosynthesis
of nitric oxide
 Signal pathway of nitric oxide
 cNOS in cardiomyocyte
Biosynthesis of Nitric
Oxide
NOS
L-arginine
L-citrulline
NO
NOS-I
NOS
nNOS
low-output
NOS-II
iNOS
high-output
NOS-III
eNOS
low-output
cNOS
Ca2+
dependant
Signal Pathway of Nitric
Oxide
NO
GTP
cGMP-dependent protein kinases
sGC
cGMP
cGMP-regulated phosphodiesterases
cGMP-regulated ion channels
NO
Pr-S-NO
Pr-SH
glutathione-dependent formaldehyde dehydrogenase
eNOS in Cardiomyocyte
sarcolemma M-R β-R
B2-R
Akt
NO
L-Arg
eNOS
Ca2+
caveolin-3
calmodulin
nNOS in Cardiomyocyte
nNOS localizes to cardiac SR
nNOS coimmunoprecipitates with the RYR
nNOS influences SR Ca2+ cycling
Part I
Nitric Oxide and
Cardiomyocyte Contractility
eNOS and Heart
Contractility
eNOS transgenic mice with very high eNOS activity
exhibit inhibitory function in cardiac myocyte contractility.
F. Brunner, P. Andrew, G. Wölkart, et al. Myocardial Contractile Function and Heart Rate in
Mice With Myocyte-Specific Overexpression of Endothelial Nitric Oxide Synthase.
Circulation 2001;104;3097-3102
eNOS and Heart
Contractility
eNOS transgenic mice with very high eNOS activity
exhibit inhibitory function in cardiac myocyte contractility
stimulated by isoprenaline.
Paul B. Massion, Chantal Dessy, Fanny Desjardins, et al.Cardiomyocyte-Restricted
Overexpression of Endothelial Nitric Oxide Synthase (NOS3) Attenuates -Adrenergic
Stimulation and Reinforces Vagal Inhibition of Cardiac Contraction. Circulation
eNOS and Heart
Contractility
eNOS transgenic mice with low eNOS activity improvement
exhibit stimulatory function in cardiac myocyte contractility.
Jun Ren, Xiaochun Zhang, Glenda I. Scott,et al. Adenovirus Gene Transfer of Recombinant
Endothelial Nitric Oxide Synthase Enhances Contractile Function in Ventricular Myocytes. J
Cardiovasc Pharmacol 2004;43:171–177
eNOS and Heart
Contractility
Ca2+
Β1/2R
β3R
eNOS
RYR
cAMP
L-Ca
NO
NO
PKG
sGC
PDE5
GTP
cGMP
cGMP-stimulated cAMPphosphodiesterase
nNOS and Heart
Contractility
nNOS inhibited or knocked out mice exhibit a significant enhance
in cardiomyocyte contractility.
Claire E. Sears, Simon M. Bryant, Euan A. Ashley,et al. Cardiac Neuronal Nitric Oxide
Synthase Isoform Regulates Myocardial Contraction and Calcium Handling. Circ. Res.
2003;92;52-59;
nNOS and Heart
Contractility
nNOS inhibited or knocked out mice exhibit a significant enhance
in cardiomyocyte contractility stimulated by isoproterenol.
Euan A. Ashley, Claire E. Sears, Simon M. Bryant, et al. Cardiac Nitric Oxide Synthase
1 Regulates Basal and beta-Adrenergic Contractility in Murine Ventricular Myocytes.
Circulation 2002;105;3011-3016
iNOS in Heart Failure
iNOS is highly expressed in
compensated or decompensated
failed heart. The activity is
significantly higher than normal.
iNOS in Heart Failure
Specific inhibitor of iNOS 1400W can
significantly enhance the contractility of
compensated or decompensated mice hearts but
don’t show any difference with sham-treated mice.
iNOS in Heart Failure
A
B
Four indexes of cardiac myocyte function of
decompensated heart failure can be improved by
1400W. A, Rate of [Ca2]i activation; B, rate of [Ca2]i D
relaxation; C, myocyte shortening velocity; and D,
myocyte relaxation velocity.
Olga Gealekman, Zaid Abassi, Irit Rubinstein, et al. Role of
Myocardial Inducible Nitric Oxide Synthase in Contractile
Dysfunction and –Adrenergic Hyporesponsiveness in Rats With
Experimental Volume-Overload Heart Failure. Circulation
2002;105;236-243
C
nNOS in Heart Failure
In heart failure cardiac
myocyte, nNOS is greatly
upregulated and translocated
to the sarcolemma, binding to
cavelolin-3.
nNOS in Heart Failure
After stimulated by beta-adrenin, failed hearts exhibit
significant weak systole and diastole function, which can be
reversed by L-NVIO.
Jennifer K. Bendall, Thibaud Damy, Philippe Ratajczak, et al. Role of Myocardial
Neuronal Nitric Oxide Synthase–Derived Nitric Oxide in -Adrenergic
Hyporesponsiveness After Myocardial Infarction–Induced Heart Failure in Rat.
Circulation 2004;110;2368-2375;
Part II
Nitric Oxide and
Cardiomyocyte Apoptosis
NO Enhancing
Cardiomyocyte Apoptosis
DETA/NO can enhance cardiac myocyte apoptosis in a time
and dose dependant manner. This is via cytochrome c and
caspase signaling pathway.
Takamichi Uchiyama, et al. Nitric Oxide Induces Caspase-dependent
Apoptosis and Necrosis in Neonatal Rat Cardiomyocytes. J Mol Cell Cardiol
34, 1049-1061 (2002)
NO Enhancing
Cardiomyocyte Apoptosis
Bak/bcl-2
NO can upregulate bak/bcl-2 ratio and induce cardiomyocyte
apoptosis.
Douglas J. Ing, et al. Modulation of Cytokine-Induced Cardiac Myocyte Apoptosis by Nitric
Oxide, Bak, and Bcl-x. Circ. Res. 1999;84;21-33
NO Reducing
Cardiomyocyte Apoptosis
NO can reduce cardiomyocyte apoptosis in
a doze and time dependant manner via Snitrosylating caspases.
Yasuhiro Maejima, et al. Nitric oxide inhibits myocardial
apoptosis by preventing caspase-3 activity via S-nitrosylation.
Journal of Molecular and Cellular Cardiology 38 (2005) 163–
174
NO Reducing
Cardiomyocyte Apoptosis
NO donor can
reduce infarct size
after I/R injury by
decreasing mPTP
opening and
upregulating Bcl-2
expression in
cardiomyocyte.
Guangwu Wang, et al. Nitric oxide donors protect murine myocardium against
infarction via modulation of mitochondrial permeability transition.
Am J Physiol Heart Circ Physiol 288:1290-1295, 2005.
NO and Cardiomyocyte
Apoptosis
Habib M. Razavi, et al. Modulation of apoptosis by nitric oxide: implications in
myocardial ischemia and heart failure. Pharmacology & Therapeutics 106 (2005)
147– 162
iNOS Inducing Apoptosis
in Heart Failure
iNOS is highly expressed in
infarcted hearts and the ratio of
apoptotic cardiomyocytes is higher
in WT mice than iNOS KO mice.
Sam, F., Sawyer, D. B., Xie, Z., Chang, D. L., Ngoy, S., Brenner, D. A., et al. (2001). Mice
lacking inducible nitric oxide synthase have improved left ventricular contractile function and
reduced apoptotic cell death late after myocardial infarction. Circ Res 89, 351– 356.
eNOS Reducing Apoptosis
in Heart Failure
eNOS KO mice exhibit more
apoptosis than WT mice and
are easier to develop HF.
Qingping Feng, et al. Development of Heart
Failure and Congenital Septal Defects in Mice
Lacking Endothelial Nitric Oxide Synthase.
Circulation 2002;106;873-879
Part III
Nitric Oxide and
Cardiomyocyte
Hypertrophy
Definition &
Classification of
Myocardial Hypertrophy



Growth of the heart occurs by hypertrophy,
i.E. Increases in cardiac myocyte size
In pressure-overload hypertrophy,
additional sarcomeres are assembled in
parallel, leading to thicker myocytes and to a
concentric pattern of ventricular
hypertrophy.
In contrast, in volume overload hypertrophy,
additional sarcomeres are assembled in
series, leading to longer myocytes and
ventricular dilatation (eccentric
hypertrophy).
Signaling Pathways in
Pressure Overload
Myocardial Hypertrophy
Tibor Kempf, Kai C. Wollert. Nitric oxide
and the enigma of cardiac hypertrophy.
BioEssays 26:608–615, 2004.
Denise Hilfiker-Kleiner, et al. Molecular
Mechanisms in Heart Failure: Focus on
Cardiac Hypertrophy, Inflammation,
Angiogenesis, and Apoptosis. J Am Coll
Cardiol 2006;48:A56–66
Inhibition of Cardiac
Hypertrophy
by Nitric Oxide
eNOS and nNOS can prevent
cardiomyocyte hypertrophy
Lili A. Barouch, et al. Nitric oxide regulates
the heart by spatial confinement of nitric
oxide synthase isoforms.
NATURE VOL 416 21 MARCH 2002
Denise Hilfiker-Kleiner, et al. Molecular
Mechanisms in Heart Failure: Focus on
Cardiac Hypertrophy, Inflammation,
Angiogenesis, and Apoptosis. J Am Coll
Conclusion



NO is an intriguing gas signal molecule.
Low doze of NO synthesized by eNOS or
nNOS usually leads to benefit results:
enhancing contractility, reducing apoptosis
and decompensatory hypertrophy.
High doze of NO synthesized by iNOS or too
much expressed eNOS or nNOS, on the
contrary, usually leads to deleterious results:
reducing contractility, enhancing apoptosis
and compensatory hypertrophy.
nNOS and Heart
Contractility
Claire E. Sears, Simon
M. Bryant, Euan A.
Ashley,et al. Cardiac
Neuronal Nitric Oxide
Synthase Isoform
Regulates Myocardial
Contraction and
Calcium Handling. Circ.
Res. 2003;92;52-59