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
Figure 1
Figure 2
Figure 3
Figure 4
Figure 5
Figure 6
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).
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).
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).
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 failure,
and may lead to the development of novel treatments for
heart failure. Glycogen synthase kinase-3 (GSK-3) is an
important negative regulator of cardiac hypertrophy (15)
(Figure 6). We have shown recently that inhibition of
GSK-3 during hypertrophy may be protective (16). We are
currently focusing 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.
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 failure,
and may lead to the development of novel treatments for
heart failure. Glycogen synthase kinase-3 (GSK-3) is an
important negative regulator of cardiac hypertrophy (15)
(Figure 6). We have shown recently that inhibition of
GSK-3 during hypertrophy may be protective (16). We are
currently focusing 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.
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
failure, using state of the art molecular biology approaches.
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.
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
failure, using state of the art molecular biology approaches.
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.
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
oxidative phosphorylation (6). In addition, Trx1
reduces disulfide bonds in class II histone
deacetylases, critical regulators of cardiac
hypertrophy, thereby inhibiting cardiac hypertrophy
(7). In collaboration with the proteomic core facility,
we are actively investigating molecular targets of
Trx1.
(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
oxidative phosphorylation (6). In addition, Trx1
reduces disulfide bonds in class II histone
deacetylases, critical regulators of cardiac
hypertrophy, thereby inhibiting cardiac hypertrophy
(7). In collaboration with the proteomic core facility,
we are actively investigating molecular targets of
Trx1.
Autophagy is an intracellular bulk degradation process
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).
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).