Junichi Sadoshima, Ph.D., M.D.
Professor

SIGNAL TRANSDUCTION MECHANISMS OF THE CARDIOVASCULAR SYSTEM

Although enlargement of cardiac myocytes, termed cardiac hypertrophy, is observed in many forms of heart disease, 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. This laboratory studies the signaling mechanisms in the heart regulating 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 KO mice are routinely generated. This laboratory has independent setups for ES cell culture and mouse surgery/physiology. Genomic and proteomic analyses are routinely conducted through in-house collaborations.

One of the major subjects of study in this laboratory is to study the function of mammalian sterile 20 like kinase (Mst1), a serine threonine kinase, in the heart. We have identified that Mst1 is 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, 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 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.

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. Trx1 is activated by stress and plays a protective role in the heart (3) . We have shown that Trx1 negatively regulates pathological hypertrophy (4) and increases mitochondrial function through increased expression of genes involved in the TCA cycle and oxidative phosphorylation (5) . Our recent work suggests that Trx1 reduces disulfide bonds in a critical regulator of cardiac hypertrophy, thereby inhibiting cardiac hypertrophy (coming soon). In collaboration with the proteomic core facility, we are actively investigating molecular targets of Trx1.

Another important subject of study in this laboratory is the role of longevity factors in mediating cardioprotection in the heart (6) . In lower organisms, activation of molecular mechanisms mediating extension of lifespan confers stress resistance to the organism. We hypothesized that activation of known longevity mechanisms in the heart may make the heart stress resistant. 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 makes the heart resistant to oxidative stress (7) . We are currently focusing on the molecular function of Sirt1 and Sirt3 in the heart. In addition, this laboratory also studies the role of other longevity mechanisms, such as Trx1, adenylyl cyclase type 5 KO and AMP-dependent protein kinase (AMPK).

Autophagy is an intracellular bulk degradation process whereby cytoplasmic proteins and organelles are degraded and recycled through lysosomes (8) . Interestingly, autophagy is required for lifespan extension in response to dietary stress in C elegans, suggesting that autophagy could be another example in which a mechanism for lifespan extension induces protection against stress. In the heart, autophagy plays a homeostatic role at basal levels, and the absence of autophagy causes cardiac dysfunction and the development of cardiomyopathy. Autophagy is induced during myocardial ischemia and further enhanced by reperfusion. 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 (9) . We are currently investigating the role of autophagy during cardiac stress.

Cardiac hypertrophy is regulated not only by positive regulators but also by negative regulators (10) . 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 treatment for heart failure. Glycogen synthase kinase-3 (GSK-3) is an important negative regulator for cardiac hypertrophy (11) . We have shown recently that inhibition of GSK-3 during hypertrophy may be protective (12) . We are currently focusing on the contrasting cardiac functions of the GSK-3 isoforms, namely GSK-3 a and GSK-3 b , in the heart (7) . GSK-3 is a critical regulator of the canonical Wnt signaling pathway. 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 .

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.   Ago, T., and Sadoshima, J. 2006. Thioredoxin and ventricular remodeling. J Mol Cell Cardiol 41:762-773.

4.   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.

5.   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.

6.   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.

7.   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.

8.   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.

9.   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.

10.   Hardt, S.E., and Sadoshima, J. 2004. Negative regulators of cardiac hypertrophy. Cardiovasc Res 63:500-509.

11.   Hardt, S.E., and Sadoshima, J. 2002. Glycogen synthase kinase-3beta: a novel regulator of cardiac hypertrophy and development. Circ Res 90:1055-1063.

12.   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.