BADERC-Anthony Rosenzweig

Anthony Rosenzweig, M.D.

Signaling Mechanisms in Cardiovascular Disease

The Rosenzweig laboratory has focused on the use of genetic models – both through somatic gene transfer and germline manipulation – to address important questions relevant to the two most common forms of heart disease: heart failure and atherosclerotic vascular disease. In both settings, research has focused on signaling mechanisms important to the pathophysiology of these conditions.

Heart Failure: Dr. Rosenzweig’s laboratory was the first to use somatic gene transfer to create models of heart failure and to document the feasibility of manipulating global ventricular function through in vivo cardiac gene transfer (PNAS, 1998). A particular focus has been pathways controlling cardiomyocyte survival and growth. These studies first demonstrated a critical role for PI 3-kinase and Akt signaling pathways in promoting cardiomyocyte survival and function (Circulation, 1999, 2001, JBC 2002a). Transcript profiling in a genetic model of cardiac hypertrophy also identified dramatic upregulation of myostatin, a potent negative regulator of skeletal muscle growth not previously recognized to play a role in the heart (JBC, 2002b). Subsequent work provided the first evidence that myostatin regulates cardiomyocyte growth in vitro and in vivo through modulation of Akt signaling (Circulation Research, 2006), a finding which may have important implications for understanding the effects of myostatin in other systems including skeletal muscle growth and metabolism, as well as for upcoming clinical trials of myostatin inhibition. Interestingly, genetic deletion of myostatin led to improved function and metabolic profiles in senescent mice without an increase in cardiac hypertrophy (Aging Cell, in press), suggesting that myostatin may contribute to the decline in cardiovascular function seen with aging. The laboratory has also been interested in identifying Akt-independent pathways (JCI, 2005), such as SGK1 (Circulation, 2005) using a combination of traditional biochemical approaches and high throughput screens, such as transcript profiling. A growing interest in the laboratory spurred on in part by interactions with BADERC is the intersection of these pro-survival signaling pathways with those controlling cardiac metabolism (Cell Metabolism, 2005; AJP, 2006; PNAS, 2006) and this topic forms the basis for an international LeDucq Foundation Network of Research Excellence, for which Dr. Rosenzweig serves as the American Coordinator.

Vascular Biology/Inflammation:
The role of vascular endothelium in both inter- and intracellular inflammatory signaling has been another major interest in the laboratory. Using somatic gene transfer, the Rosenzweig laboratory has established realistic models both in vitro and in vivo to dissect the key pathways modulating leukocyte-endothelial interaction and to elucidate the roles of these subsets in disease pathogenesis including a novel mechanism by which chemokines induce monocyte recruitment: conversion of monocyte rolling to firm adhesion (Nature 1999). This ability to convert leukocyte rolling to arrest appears to be an important, general mechanism of chemokine action with relevance to a wide variety of inflammatory disorders. Studies on the intracellular mechanisms involved in endothelial activation have recently focused on modulation of NF-kB activation. Using somatic gene transfer, the Rosenzweig laboratory has identified novel inhibitors of NF-kB signaling in both cardiomyocytes and endothelial cells that may prove useful as therapeutic targets (Circulation, 2003; AJP, 2005). In addition, endothelial-specific knockouts of IKKb (the dominant kinase mediating NF-kB activation) have recently been generated in the laboratory and point to unanticipated effects of NF-kB in the cardiovascular system regulating not only inflammation but angiogenesis and permeability (submitted). Collaborative studies led by Drs. Zolt Arany and Bruce Spiegelman have recently identified a novel HIF-independent pathway of vasculogenesis that appears to play an important role in the response to ischemic injury (Nature, 2008) via the transcriptional co-activator, PGC-1a. Given the role of PGC-1a as a master regulator of metabolism and mitochondrial biogenesis, as well as the observation by others that PGC-1a-dependent transcripts are decreased in diabetic skeletal muscle, its role in vasculogenesis may have direct relevance for diabetic vascular disease and ischemia injury.

References:

Hajjar RJ, Schmidt S, Matsui T, Guerrero L, Lee K-H, Gwathmey JK, Dec GW, Semigran MJ, Rosenzweig A. Modulation of ventricular function through gene transfer in vivo . Proceedings of the National Academy of Sciences (USA), 1998;95:5251-5256.
Matsui TM, Li L, Del Monte F, Franke T, Fukui Y, Hajjar RJ, Rosenzweig A. Adenoviral gene transfer of activated PI-3 kinase and Akt prevents apoptosis of hypoxic cardiomyocytes in vitro. Circulation, 1999; 100:2373-2379.
Matsui T, Tao J, del Monte F, Lee KH, Li L, Picard M, Force TL, Franke T, Hajjar RJ, Rosenzweig A. Akt activation preserves cardiac function and prevents injury after transient cardiac ischemia in vivo. Circulation 2001;104:330-335.
Matsui T, Li L, Wu JC, Cook SA, Nagoshi T, Picard M, Liao R, Rosenzweig A. Phenotypic spectrum caused by transgenic overexpression of activated Akt in the heart. Journal of Biological Chemistry. 2002;277:22896-22901.
Cook SA, Matsui T, Li L, Rosenzweig A. Transcriptional effects of chronic Akt activation in the heart. Journal of Biological Chemistry. 2002;277:22528-22533.
Cook SA, Novikov M, Ahn Y, Matsui T, Rosenzweig A. A20 is dynamically regulated in the heart and inhibits the hypertrophic response. Circulation, 2003; 108:664-7.
Nagoshi, T., Matsui, T., Aoyama, T., Leri, A., Anversa, P., Li, L., Ogawa, W., Del Monte, F., Gwathmey, J.K., Grazette, L., Hemmings B, Kass D, Champion H, Rosenzweig A. 2005. PI3K rescues the detrimental effects of chronic Akt activation in the heart during ischemia/reperfusion injury. Journal of Clinical Investigation 115:2128-2138.
Chao, W., Shen, Y., Li, L., Zhao, H., Meiler, S.E., Cook, S.A., and Rosenzweig, A. 2005. Fas-associated Death Domain Protein Inhibits TNF-{alpha} mediated NF-{kappa}B Activation in Cardiomyocytes. Am J Physiol Heart Circ Physiol.289:H2073-80
Aoyama, T., Matsui, T., Novikov, M., Park, J., Hemmings, B., and Rosenzweig, A. 2005. Serum and glucocorticoid-responsive kinase-1 regulates cardiomyocyte survival and hypertrophic response. Circulation 111:1652-1659.
Arany Z, He H, Lin J, Hoyer K, Handschin C, Toka O, Ahmad F, Matsui T, Chin S, Wu P, Rybkin I, Shelton J, Manieri M, Cinti S, Schoen F, Bassel-Duby R, Rosenzweig A, Ingwall J, Spiegelman BM. 2005. Transcriptional coactivator PGC-1alpha controls the energy state and contractile function of cardiac muscle. Cell Metabolism 1:259-271
Morissette, M.R., Cook, S.A., Foo, S.Y., McKoy, G. Ashida, N, Novikov, N, Scherrer-Crosbie, M., Li, L., Matsui, T., Brooks, G., Rosenzweig, A. Myostatin regulates cardiomyocyte growth through modulation of Akt signaling. Circulation Research 2006. 99(1): p. 15-24.
Matsui, T., Nagoshi, T., Hong, E. G., Luptak, I., Hartil, K., Li, L., Gorovits, N., Charron, M. J., Kim, J. K., Tian, R., and Rosenzweig, A. (2006). Effects of chronic Akt activation on glucose uptake in the heart. Am J Physiol Endocrinol Metab 290, E789-797
Arany, Z., Novikov, M., Chin, S., Ma, Y., Rosenzweig, A., Spiegelman, B.M. Transverse aortic constriction leads to accelerated heart failure in mice lacking PGC-1α. Proceedings of the National Academy of Sciences (USA) 2006. 103(26): p. 10086-91.
Arany Z, Foo SY, Ma Y, Ruas J, Bommi-Reddy A, Girnun G, Cooper M, Laznik D, Rosenzweig A, Spiegelman BM. HIF-independent regulation of VEGF and angiogenesis by the metabolic sensor and transcriptional coactivator PGC-1α. Nature, 2008. 451(7181):1008-1012






			Anthony Rosenzweig, M.D. Signaling Mechanisms in Cardiovascular Disease The Rosenzweig laboratory has focused on the use of genetic models – both through somatic gene transfer and germline manipulation – to address important questions relevant to the two most common forms of heart disease: heart failure and atherosclerotic vascular disease. In both settings, research has focused on signaling mechanisms important to the pathophysiology of these conditions. Heart Failure: Dr. Rosenzweig’s laboratory was the first to use somatic gene transfer to create models of heart failure and to document the feasibility of manipulating global ventricular function through in vivo cardiac gene transfer (PNAS, 1998). A particular focus has been pathways controlling cardiomyocyte survival and growth. These studies first demonstrated a critical role for PI 3-kinase and Akt signaling pathways in promoting cardiomyocyte survival and function (Circulation, 1999, 2001, JBC 2002a). Transcript profiling in a genetic model of cardiac hypertrophy also identified dramatic upregulation of myostatin, a potent negative regulator of skeletal muscle growth not previously recognized to play a role in the heart (JBC, 2002b). Subsequent work provided the first evidence that myostatin regulates cardiomyocyte growth in vitro and in vivo through modulation of Akt signaling (Circulation Research, 2006), a finding which may have important implications for understanding the effects of myostatin in other systems including skeletal muscle growth and metabolism, as well as for upcoming clinical trials of myostatin inhibition. Interestingly, genetic deletion of myostatin led to improved function and metabolic profiles in senescent mice without an increase in cardiac hypertrophy (Aging Cell, in press), suggesting that myostatin may contribute to the decline in cardiovascular function seen with aging. The laboratory has also been interested in identifying Akt-independent pathways (JCI, 2005), such as SGK1 (Circulation, 2005) using a combination of traditional biochemical approaches and high throughput screens, such as transcript profiling. A growing interest in the laboratory spurred on in part by interactions with BADERC is the intersection of these pro-survival signaling pathways with those controlling cardiac metabolism (Cell Metabolism, 2005; AJP, 2006; PNAS, 2006) and this topic forms the basis for an international LeDucq Foundation Network of Research Excellence, for which Dr. Rosenzweig serves as the American Coordinator. Vascular Biology/Inflammation: The role of vascular endothelium in both inter- and intracellular inflammatory signaling has been another major interest in the laboratory. Using somatic gene transfer, the Rosenzweig laboratory has established realistic models both in vitro and in vivo to dissect the key pathways modulating leukocyte-endothelial interaction and to elucidate the roles of these subsets in disease pathogenesis including a novel mechanism by which chemokines induce monocyte recruitment: conversion of monocyte rolling to firm adhesion (Nature 1999). This ability to convert leukocyte rolling to arrest appears to be an important, general mechanism of chemokine action with relevance to a wide variety of inflammatory disorders. Studies on the intracellular mechanisms involved in endothelial activation have recently focused on modulation of NF-kB activation. Using somatic gene transfer, the Rosenzweig laboratory has identified novel inhibitors of NF-kB signaling in both cardiomyocytes and endothelial cells that may prove useful as therapeutic targets (Circulation, 2003; AJP, 2005). In addition, endothelial-specific knockouts of IKKb (the dominant kinase mediating NF-kB activation) have recently been generated in the laboratory and point to unanticipated effects of NF-kB in the cardiovascular system regulating not only inflammation but angiogenesis and permeability (submitted). Collaborative studies led by Drs. Zolt Arany and Bruce Spiegelman have recently identified a novel HIF-independent pathway of vasculogenesis that appears to play an important role in the response to ischemic injury (Nature, 2008) via the transcriptional co-activator, PGC-1a. Given the role of PGC-1a as a master regulator of metabolism and mitochondrial biogenesis, as well as the observation by others that PGC-1a-dependent transcripts are decreased in diabetic skeletal muscle, its role in vasculogenesis may have direct relevance for diabetic vascular disease and ischemia injury. References: Hajjar RJ, Schmidt S, Matsui T, Guerrero L, Lee K-H, Gwathmey JK, Dec GW, Semigran MJ, Rosenzweig A. Modulation of ventricular function through gene transfer in vivo . Proceedings of the National Academy of Sciences (USA), 1998;95:5251-5256. Matsui TM, Li L, Del Monte F, Franke T, Fukui Y, Hajjar RJ, Rosenzweig A. Adenoviral gene transfer of activated PI-3 kinase and Akt prevents apoptosis of hypoxic cardiomyocytes in vitro. Circulation, 1999; 100:2373-2379. Matsui T, Tao J, del Monte F, Lee KH, Li L, Picard M, Force TL, Franke T, Hajjar RJ, Rosenzweig A. Akt activation preserves cardiac function and prevents injury after transient cardiac ischemia in vivo. Circulation 2001;104:330-335. Matsui T, Li L, Wu JC, Cook SA, Nagoshi T, Picard M, Liao R, Rosenzweig A. Phenotypic spectrum caused by transgenic overexpression of activated Akt in the heart. Journal of Biological Chemistry. 2002;277:22896-22901. Cook SA, Matsui T, Li L, Rosenzweig A. Transcriptional effects of chronic Akt activation in the heart. Journal of Biological Chemistry. 2002;277:22528-22533. Cook SA, Novikov M, Ahn Y, Matsui T, Rosenzweig A. A20 is dynamically regulated in the heart and inhibits the hypertrophic response. Circulation, 2003; 108:664-7. Nagoshi, T., Matsui, T., Aoyama, T., Leri, A., Anversa, P., Li, L., Ogawa, W., Del Monte, F., Gwathmey, J.K., Grazette, L., Hemmings B, Kass D, Champion H, Rosenzweig A. 2005. PI3K rescues the detrimental effects of chronic Akt activation in the heart during ischemia/reperfusion injury. Journal of Clinical Investigation 115:2128-2138. Chao, W., Shen, Y., Li, L., Zhao, H., Meiler, S.E., Cook, S.A., and Rosenzweig, A. 2005. Fas-associated Death Domain Protein Inhibits TNF-{alpha} mediated NF-{kappa}B Activation in Cardiomyocytes. Am J Physiol Heart Circ Physiol.289:H2073-80 Aoyama, T., Matsui, T., Novikov, M., Park, J., Hemmings, B., and Rosenzweig, A. 2005. Serum and glucocorticoid-responsive kinase-1 regulates cardiomyocyte survival and hypertrophic response. Circulation 111:1652-1659. Arany Z, He H, Lin J, Hoyer K, Handschin C, Toka O, Ahmad F, Matsui T, Chin S, Wu P, Rybkin I, Shelton J, Manieri M, Cinti S, Schoen F, Bassel-Duby R, Rosenzweig A, Ingwall J, Spiegelman BM. 2005. Transcriptional coactivator PGC-1alpha controls the energy state and contractile function of cardiac muscle. Cell Metabolism 1:259-271 Morissette, M.R., Cook, S.A., Foo, S.Y., McKoy, G. Ashida, N, Novikov, N, Scherrer-Crosbie, M., Li, L., Matsui, T., Brooks, G., Rosenzweig, A. Myostatin regulates cardiomyocyte growth through modulation of Akt signaling. Circulation Research 2006. 99(1): p. 15-24. Matsui, T., Nagoshi, T., Hong, E. G., Luptak, I., Hartil, K., Li, L., Gorovits, N., Charron, M. J., Kim, J. K., Tian, R., and Rosenzweig, A. (2006). Effects of chronic Akt activation on glucose uptake in the heart. Am J Physiol Endocrinol Metab 290, E789-797 Arany, Z., Novikov, M., Chin, S., Ma, Y., Rosenzweig, A., Spiegelman, B.M. Transverse aortic constriction leads to accelerated heart failure in mice lacking PGC-1α. Proceedings of the National Academy of Sciences (USA) 2006. 103(26): p. 10086-91. Arany Z, Foo SY, Ma Y, Ruas J, Bommi-Reddy A, Girnun G, Cooper M, Laznik D, Rosenzweig A, Spiegelman BM. HIF-independent regulation of VEGF and angiogenesis by the metabolic sensor and transcriptional coactivator PGC-1α. Nature, 2008. 451(7181):1008-1012