References
1. Yamamoto, S., Yang, G., Zablocki, D., Liu, J., Hong, C., Kim, S.J., Soler, S., Odashima, M., Thaisz, J., Yehia, G., Molina, C.A., Yatani, A., Vatner,
D.E., Vatner, S.F., and Sadoshima, J. 2003. Activation of Mst1 causes dilated cardiomyopathy by stimulating apoptosis without compensatory
ventricular myocyte hypertrophy. J Clin Invest 111:1463-1474.
2. Odashima, M., Usui, S., Takagi, H., Hong, C., Liu, J., Yokota, M., and Sadoshima, J. 2007. Inhibition of endogenous Mst1 prevents apoptosis and
cardiac dysfunction without affecting cardiac hypertrophy after myocardial infarction. Circ Res 100:1344-1352.
3. Matsui, Y., Nakano, N., Shao, D., Gao, S., Luo, W., Hong, C., Zhai, P., Holle, E., Yu, X., Yabuta, N., Tao, W., Wagner, T., Nojima, H., and
Sadoshima, J. 2008. Lats2 Is a Negative Regulator of Myocyte Size in the Heart. Circ Res 103:1309-1318.
4. Ago, T., and Sadoshima, J. 2006. Thioredoxin and ventricular remodeling. J Mol Cell Cardiol 41:762-773.
5. Yamamoto, M., Yang, G., Hong, C., Liu, J., Holle, E., Yu, X., Wagner, T., Vatner, S.F., and Sadoshima, J. 2003. Inhibition of thioredoxin in the heart
increases oxidative stress and cardiac hypertrophy. J. Clin. Invest. 112:1395-1406.
6. Ago, T., Yeh, I., Yamamoto, M., Schinke-Braun, M., Brown, J.A., Tian, B., and Sadoshima, J. 2006. Thioredoxin1 upregulates mitochondrial proteins
related to oxidative phosphorylation and TCA cycle in the heart. Antioxid Redox Signal 8:1635-1650.
7. Ago, T., Liu, T., Zhai, P., Chen, W., Li, H., Molkentin, J.D., Vatner, S.F., and Sadoshima, J. 2008. A redox-dependent pathway for regulating class II
HDACs and cardiac hypertrophy. Cell 133:978-993.
8. Yan, L., Vatner, D.E., O'Connor, J.P., Ivessa, A., Ge, H., Chen, W., Hirotani, S., Ishikawa, Y., Sadoshima, J., and Vatner, S.F. 2007. Type 5 adenylyl
cyclase disruption increases longevity and protects against stress. Cell 130:247-258.
9. Hsu, C.P., Odewale, I., Alcendor, R.R., and Sadoshima, J. 2008. Sirt1 protects the heart from aging and stress. Biol Chem 389:221-231.
10. Alcendor, R.R., Gao, S., Zhai, P., Zablocki, D., Holle, E., Yu, X., Tian, B., Wagner, T., Vatner, S.F., and Sadoshima, J. 2007. Sirt1 regulates aging
and resistance to oxidative stress in the heart. Circ Res 100:1512-1521.
11. Takagi, H., Matsui, Y., and Sadoshima, J. 2007. The role of autophagy in mediating cell survival and death during ischemia and reperfusion in the
heart. Antioxid Redox Signal 9:1373-1381.
12. Matsui, Y., Kyoi, S., Takagi, H., Hsu, C.P., Hariharan, N., Ago, T., Vatner, S.F., and Sadoshima, J. 2008. Molecular mechanisms and physiological
significance of autophagy during myocardial ischemia and reperfusion. Autophagy 4:409-415.
13. Matsui, Y., Takagi, H., Qu, X., Abdellatif, M., Sakoda, H., Asano, T., Levine, B., and Sadoshima, J. 2007. Distinct Roles of Autophagy in the Heart
During Ischemia and Reperfusion. Roles of AMP-Activated Protein Kinase and Beclin 1 in Mediating Autophagy. Circ Res 100:914-922.
14. Hardt, S.E., and Sadoshima, J. 2004. Negative regulators of cardiac hypertrophy. Cardiovasc Res 63:500-509.
15. Hardt, S.E., and Sadoshima, J. 2002. Glycogen synthase kinase-3beta: a novel regulator of cardiac hypertrophy and development. Circ Res
90:1055-1063.
16. Hirotani, S., Zhai, P., Tomita, H., Galeotti, J., Marquez, J.P., Gao, S., Hong, C., Yatani, A., Avila, J., and Sadoshima, J. 2007. Inhibition of glycogen
synthase kinase 3beta during heart failure is protective. Circ. Res. 101:1164-1174.
17. Matsuda, T., Zhai, P., Maejima, Y., Hong, C., Gao, S., Tian, B., Goto, H., Takagi, H., Tamamoti-Adachi, T., Kitajima, S., and Sadoshima, J. 2008.
Phosphorylation of GSK-3a is essential for myocyte proliferation in the heart under pressure overload. Proc Natl Acad Sci U S A (in press).
18. Zhai, P., Gao, S., Holle, E., Yu, X., Yatani, A., Wagner, T., and Sadoshima, J. 2007. Glycogen synthase kinase-3alpha reduces cardiac growth
and pressure overload-induced cardiac hypertrophy by inhibition of extracellular signal-regulated kinases. J Biol Chem 282:33181-33191.
19. Zhai, P., and Sadoshima, J. 2008. Overcoming an energy crisis?: an adaptive role of glycogen synthase kinase-3 inhibition in
ischemia/reperfusion. Circ Res 103:910-913.
1. Yamamoto, S., Yang, G., Zablocki, D., Liu, J., Hong, C., Kim, S.J., Soler, S., Odashima, M., Thaisz, J., Yehia, G., Molina, C.A., Yatani, A., Vatner,
D.E., Vatner, S.F., and Sadoshima, J. 2003. Activation of Mst1 causes dilated cardiomyopathy by stimulating apoptosis without compensatory
ventricular myocyte hypertrophy. J Clin Invest 111:1463-1474.
2. Odashima, M., Usui, S., Takagi, H., Hong, C., Liu, J., Yokota, M., and Sadoshima, J. 2007. Inhibition of endogenous Mst1 prevents apoptosis and
cardiac dysfunction without affecting cardiac hypertrophy after myocardial infarction. Circ Res 100:1344-1352.
3. Matsui, Y., Nakano, N., Shao, D., Gao, S., Luo, W., Hong, C., Zhai, P., Holle, E., Yu, X., Yabuta, N., Tao, W., Wagner, T., Nojima, H., and
Sadoshima, J. 2008. Lats2 Is a Negative Regulator of Myocyte Size in the Heart. Circ Res 103:1309-1318.
4. Ago, T., and Sadoshima, J. 2006. Thioredoxin and ventricular remodeling. J Mol Cell Cardiol 41:762-773.
5. Yamamoto, M., Yang, G., Hong, C., Liu, J., Holle, E., Yu, X., Wagner, T., Vatner, S.F., and Sadoshima, J. 2003. Inhibition of thioredoxin in the heart
increases oxidative stress and cardiac hypertrophy. J. Clin. Invest. 112:1395-1406.
6. Ago, T., Yeh, I., Yamamoto, M., Schinke-Braun, M., Brown, J.A., Tian, B., and Sadoshima, J. 2006. Thioredoxin1 upregulates mitochondrial proteins
related to oxidative phosphorylation and TCA cycle in the heart. Antioxid Redox Signal 8:1635-1650.
7. Ago, T., Liu, T., Zhai, P., Chen, W., Li, H., Molkentin, J.D., Vatner, S.F., and Sadoshima, J. 2008. A redox-dependent pathway for regulating class II
HDACs and cardiac hypertrophy. Cell 133:978-993.
8. Yan, L., Vatner, D.E., O'Connor, J.P., Ivessa, A., Ge, H., Chen, W., Hirotani, S., Ishikawa, Y., Sadoshima, J., and Vatner, S.F. 2007. Type 5 adenylyl
cyclase disruption increases longevity and protects against stress. Cell 130:247-258.
9. Hsu, C.P., Odewale, I., Alcendor, R.R., and Sadoshima, J. 2008. Sirt1 protects the heart from aging and stress. Biol Chem 389:221-231.
10. Alcendor, R.R., Gao, S., Zhai, P., Zablocki, D., Holle, E., Yu, X., Tian, B., Wagner, T., Vatner, S.F., and Sadoshima, J. 2007. Sirt1 regulates aging
and resistance to oxidative stress in the heart. Circ Res 100:1512-1521.
11. Takagi, H., Matsui, Y., and Sadoshima, J. 2007. The role of autophagy in mediating cell survival and death during ischemia and reperfusion in the
heart. Antioxid Redox Signal 9:1373-1381.
12. Matsui, Y., Kyoi, S., Takagi, H., Hsu, C.P., Hariharan, N., Ago, T., Vatner, S.F., and Sadoshima, J. 2008. Molecular mechanisms and physiological
significance of autophagy during myocardial ischemia and reperfusion. Autophagy 4:409-415.
13. Matsui, Y., Takagi, H., Qu, X., Abdellatif, M., Sakoda, H., Asano, T., Levine, B., and Sadoshima, J. 2007. Distinct Roles of Autophagy in the Heart
During Ischemia and Reperfusion. Roles of AMP-Activated Protein Kinase and Beclin 1 in Mediating Autophagy. Circ Res 100:914-922.
14. Hardt, S.E., and Sadoshima, J. 2004. Negative regulators of cardiac hypertrophy. Cardiovasc Res 63:500-509.
15. Hardt, S.E., and Sadoshima, J. 2002. Glycogen synthase kinase-3beta: a novel regulator of cardiac hypertrophy and development. Circ Res
90:1055-1063.
16. Hirotani, S., Zhai, P., Tomita, H., Galeotti, J., Marquez, J.P., Gao, S., Hong, C., Yatani, A., Avila, J., and Sadoshima, J. 2007. Inhibition of glycogen
synthase kinase 3beta during heart failure is protective. Circ. Res. 101:1164-1174.
17. Matsuda, T., Zhai, P., Maejima, Y., Hong, C., Gao, S., Tian, B., Goto, H., Takagi, H., Tamamoti-Adachi, T., Kitajima, S., and Sadoshima, J. 2008.
Phosphorylation of GSK-3a is essential for myocyte proliferation in the heart under pressure overload. Proc Natl Acad Sci U S A (in press).
18. Zhai, P., Gao, S., Holle, E., Yu, X., Yatani, A., Wagner, T., and Sadoshima, J. 2007. Glycogen synthase kinase-3alpha reduces cardiac growth
and pressure overload-induced cardiac hypertrophy by inhibition of extracellular signal-regulated kinases. J Biol Chem 282:33181-33191.
19. Zhai, P., and Sadoshima, J. 2008. Overcoming an energy crisis?: an adaptive role of glycogen synthase kinase-3 inhibition in
ischemia/reperfusion. Circ Res 103:910-913.
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Current Lab Research
Story I
Cardiac hypertrophy is the enlargement of cardiac myocytes, and is
observed in many forms of heart disease. Nevertheless, increasing
lines of evidence suggest that the progression of heart failure is
determined by the balance between cell death promoting
mechanisms and cell survival/protective mechanisms, rather than
by the presence of cardiac hypertrophy alone (Figure 1). This
laboratory studies the signaling mechanisms which regulate the
growth and death of cardiac myocytes, with a particular emphasis
on those relevant to the pathogenesis of heart Transgenic mice
and knock-out (KO) mice are routinely generated, and the
laboratory has independent setups for ES cell culture and mouse
surgery/physiology. Genomic and proteomic analyses are routinely
conducted through in-house collaborations.
observed in many forms of heart disease. Nevertheless, increasing
lines of evidence suggest that the progression of heart failure is
determined by the balance between cell death promoting
mechanisms and cell survival/protective mechanisms, rather than
by the presence of cardiac hypertrophy alone (Figure 1). This
laboratory studies the signaling mechanisms which regulate the
growth and death of cardiac myocytes, with a particular emphasis
on those relevant to the pathogenesis of heart Transgenic mice
and knock-out (KO) mice are routinely generated, and the
laboratory has independent setups for ES cell culture and mouse
surgery/physiology. Genomic and proteomic analyses are routinely
conducted through in-house collaborations.
Story II
One of the major subjects of study in this laboratory is the function
of mammalian sterile 20 like kinase (Mst1), a serine threonine
kinase, in the heart. We have identified Mst1 as one of the most
prominent kinases activated when cardiac myocytes undergo
apoptosis. Using transgenic approaches, we have shown that
Mst1 strongly activates apoptosis in cardiac myocytes and that
endogenous Mst1 is involved in ischemia/reperfusion injury (1)
and the development of heart failure after myocardial infarction (2)
in the mouse heart. Unexpectedly, we found that Mst1 is also
involved in many other functions in the heart, such as inhibition of
compensatory hypertrophy, induction of endoplasmic stress and
mitochondrial dysfunction, all of which are intimately involved in
the pathogenesis of heart failure. Recent evidence suggests that
Mst1 belongs to an evolutionarily conserved signaling cascade
regulating organ size, which has been most extensively studied in
Drosophila and is called the “hippo” pathway. We have shown that
Mst1 activates Lats2, a homologue of Drosophila Wts, which in
turn plays a critical role in regulating the size of the heart (3). We
expect that both upstream regulators and downstream effectors of
Mst1 and their functions in mammalian cells, including cardiac
myocytes, will be identified in the next few years (Figure 2).
of mammalian sterile 20 like kinase (Mst1), a serine threonine
kinase, in the heart. We have identified Mst1 as one of the most
prominent kinases activated when cardiac myocytes undergo
apoptosis. Using transgenic approaches, we have shown that
Mst1 strongly activates apoptosis in cardiac myocytes and that
endogenous Mst1 is involved in ischemia/reperfusion injury (1)
and the development of heart failure after myocardial infarction (2)
in the mouse heart. Unexpectedly, we found that Mst1 is also
involved in many other functions in the heart, such as inhibition of
compensatory hypertrophy, induction of endoplasmic stress and
mitochondrial dysfunction, all of which are intimately involved in
the pathogenesis of heart failure. Recent evidence suggests that
Mst1 belongs to an evolutionarily conserved signaling cascade
regulating organ size, which has been most extensively studied in
Drosophila and is called the “hippo” pathway. We have shown that
Mst1 activates Lats2, a homologue of Drosophila Wts, which in
turn plays a critical role in regulating the size of the heart (3). We
expect that both upstream regulators and downstream effectors of
Mst1 and their functions in mammalian cells, including cardiac
myocytes, will be identified in the next few years (Figure 2).
Figure 1
Figure 2
Story III
We also investigate the function of thioredoxin
1 (Trx1) in the heart. Trx1 is a 12kD
anti-oxidant which reduces proteins with
disulfide bonds through a thiol-disulfide
exchange reaction (Figure 3). Trx1 is activated
by stress and plays a protective role in the
heart (4). We have shown that Trx1 negatively
regulates pathological hypertrophy (5) and
increases mitochondrial function through
increased expression of genes involved in the
TCA cycle and (7). In collaboration with the
proteomic core facility, we are actively
investigating molecular targets of Trx1.
1 (Trx1) in the heart. Trx1 is a 12kD
anti-oxidant which reduces proteins with
disulfide bonds through a thiol-disulfide
exchange reaction (Figure 3). Trx1 is activated
by stress and plays a protective role in the
heart (4). We have shown that Trx1 negatively
regulates pathological hypertrophy (5) and
increases mitochondrial function through
increased expression of genes involved in the
TCA cycle and (7). In collaboration with the
proteomic core facility, we are actively
investigating molecular targets of Trx1.
Figure 3
Story IV
Another important subject of study is the role of
longevity factors in mediating cardioprotection in the
heart (8). In lower organisms, activation of molecular
mechanisms mediating extension of lifespan confers
stress resistance to the organism. We hypothesize
that activation of known longevity mechanisms in the
heart may make the heart more stress resistant
(Figure 4) (9). Sirt1 is an NAD+-dependent class III
histone deacetylase which plays an important role in
mediating lifespan extension in response to caloric
restriction in lower organisms. In the heart, Sirt1 is
upregulated by stress, and mild to moderate
expression of Sirt1 retards aging of the heart and
increases the heart’s resistance to oxidative stress
(10). We are currently focusing on the molecular
functions of Sirt1 and Sirt3 in the heart, as well as
studying the roles of other longevity mechanisms,
such as Trx1, adenylyl cyclase type 5 KO and AMP-
dependent protein kinase (AMPK).
longevity factors in mediating cardioprotection in the
heart (8). In lower organisms, activation of molecular
mechanisms mediating extension of lifespan confers
stress resistance to the organism. We hypothesize
that activation of known longevity mechanisms in the
heart may make the heart more stress resistant
(Figure 4) (9). Sirt1 is an NAD+-dependent class III
histone deacetylase which plays an important role in
mediating lifespan extension in response to caloric
restriction in lower organisms. In the heart, Sirt1 is
upregulated by stress, and mild to moderate
expression of Sirt1 retards aging of the heart and
increases the heart’s resistance to oxidative stress
(10). We are currently focusing on the molecular
functions of Sirt1 and Sirt3 in the heart, as well as
studying the roles of other longevity mechanisms,
such as Trx1, adenylyl cyclase type 5 KO and AMP-
dependent protein kinase (AMPK).
Figure 4
Story V
whereby cytoplasmic proteins and organelles are degraded
and recycled through lysosomes (11). Interestingly,
autophagy is required for lifespan extension in response to
dietary stress in C elegans, suggesting that autophagy
could be yet another example in which a lifespan extension
mechanism induces protection against stress. In the heart,
basal levels of autophagy play a homeostatic role, and the
absence of autophagy causes cardiac dysfunction and the
development of cardiomyopathy. On the other hand,
myocardial ischemia and reperfusion elicit conditions which
strongly induce autophagy, including energy starvation,
damage to intracellular organelles, protein aggregation,
oxidative stress and ER stress (Figure 5). Using a mouse
model of ischemia/reperfusion, we are studying both the
signaling mechanisms and the functional significance of
autophagy in the heart. We have shown recently that,
although induction of autophagy during the ischemic phase
is protective, further enhancement of autophagy during the
reperfusion phase may induce cell death and appears to be
detrimental in the heart (12, 13).
and recycled through lysosomes (11). Interestingly,
autophagy is required for lifespan extension in response to
dietary stress in C elegans, suggesting that autophagy
could be yet another example in which a lifespan extension
mechanism induces protection against stress. In the heart,
basal levels of autophagy play a homeostatic role, and the
absence of autophagy causes cardiac dysfunction and the
development of cardiomyopathy. On the other hand,
myocardial ischemia and reperfusion elicit conditions which
strongly induce autophagy, including energy starvation,
damage to intracellular organelles, protein aggregation,
oxidative stress and ER stress (Figure 5). Using a mouse
model of ischemia/reperfusion, we are studying both the
signaling mechanisms and the functional significance of
autophagy in the heart. We have shown recently that,
although induction of autophagy during the ischemic phase
is protective, further enhancement of autophagy during the
reperfusion phase may induce cell death and appears to be
detrimental in the heart (12, 13).
Figure 5
Story VI
Finally, cardiac hypertrophy is regulated by
negative, as well as positive, regulators (14).
Studying the mechanisms by which the endogenous
negative regulators inhibit hypertrophy would
provide useful information regarding the
pathogenesis of cardiac hypertrophy and heart
treatments for heart failure. Glycogen synthase
kinase-3 (GSK-3) is an important negative regulator
of cardiac hypertrophy (15) (Figure 6). We have on
the contrasting cardiac functions of the GSK-3
isoforms, namely GSK-3a and GSK-3b, in the heart
(17-19). In addition, we are also studying the effect
of GSK-3 modulation upon mesenchymal stem cell
differentiation into the cardiac myocyte lineage
following myocardial infarction in vivo.
negative, as well as positive, regulators (14).
Studying the mechanisms by which the endogenous
negative regulators inhibit hypertrophy would
provide useful information regarding the
pathogenesis of cardiac hypertrophy and heart
treatments for heart failure. Glycogen synthase
kinase-3 (GSK-3) is an important negative regulator
of cardiac hypertrophy (15) (Figure 6). We have on
the contrasting cardiac functions of the GSK-3
isoforms, namely GSK-3a and GSK-3b, in the heart
(17-19). In addition, we are also studying the effect
of GSK-3 modulation upon mesenchymal stem cell
differentiation into the cardiac myocyte lineage
following myocardial infarction in vivo.
Figure 6