MAJOR RESEARCH INTERESTS:
Research in the Walsh laboratory investigates the signaling- and transcriptional-regulatory mechanisms that control both normal and pathological tissue growth in the cardiovascular system. Our studies were among the first to document that the eNOS/PI3-kinase/Akt/GSK/Forkhead signaling axis is of critical importance in the regulation of the cardiovascular system. Signaling through this pathway controls cellular enlargement (hypertrophy), cell death (apoptosis), and blood vessel recruitment and growth (angiogenesis). We have shown that the PI3-kinase/Akt/eNOS/GSK/Forkhead signaling axis regulates multiple steps critical in angiogenesis including endothelial cell apoptosis, differentiation, nitric oxide production and migration. We have also shown that some of these signaling steps are important for cardiac hypertrophy during normal postnatal development and that they regulate myocyte survival in models of heart disease.
Major projects in the Walsh laboratory analyze mechanisms of inter-tissue communication within the cardiovascular system and how these regulatory mechanisms are perturbed by obesity-induced metabolic dysfunction. Using mouse genetic models we have found that perturbations in crosstalk mechanisms between cardiac myocytes and vascular endothelial cells contribute to the transitions from compensated hypertrophy to heart failure. Factors involved in this regulation include VEGF, Fstl1, Fstl3 and Activin-A. Subsequent studies in patient populations have shown that at least one of these factors (Fstl1) is upregulated in clinical heart failure and is predictive of mortality in patients with acute coronary syndrome. Related studies have examined how alterations in the expression of adipocyte-derived cytokines, referred to as adipokines, interfere with normal signaling within the cardiovascular system and thereby contribute to cardiovascular disease. Adiponectin is an anti-inflammatory adipokine that is down-regulated in obesity. Studies by the Walsh laboratory were first to show that adiponectin directly acts on the heart and vasculature as a cardio-protective factor. Recently we found that Sfrp5/Wnt5a regulatory axis functions to control systemic metabolism through regulation of adipose tissue inflammation. Finally, our laboratory is examining how age-associated loss of skeletal muscle mass affects metabolic and cardiovascular function, and is exploring the possibility that muscle-secreted factors (myokines) confer some of the benefits of exercise training on cardiovascular and metabolic diseases.
A new project in the laboratory is investigating the role of mitochondrial dynamics in controlling the functions of cardiovascular tissues. Mitochondria can form elongated tubule networks or small spherical organelles depending upon the needs of the cell. These morphological transitions occur through fusion and fission of the mitochondrial membranes. Fusion may function to allow for the exchange of metabolites and DNA throughout the mitochondrial network. Conversely, fission may function to allow for the transport of small mitochondria to distant parts of the cell or in the process of removing damaged mitochondria through a "mitophagic" mechanism. We are addressing these questions by focusing on the mitochondrial shaping proteins mitofusin-1 and mitofusin-2 in cell culture models and genetically-engineered mice.
Selected Peer-reviewed Publications (Selected from 339 publications as of April 2014)
I. Shimizu, T. Aprahamian, R. Kikuchi, A. Shimizu, K. N. Papanicolaou, S. Maclauchlan, S. Maruyama, K. Walsh (2014). Vascular rarefaction mediates whitening of brown fat in obesity. J. Clin. Invest. [Epub ahead of print Apr 8] doi: 10.1172/JCI71643 (PMC in progress).
J. L. Parker-Duffen, K. Nakamura, M. Silver, M. A. Zuriaga, S. MacLauchlan, T. R. Aprahamian, K. Walsh. (2014). Divergent roles for AdipoR1 and AdipoR2 in mediating revascularization and metabolic dysfunction in vivo. J. Biol. Chem. [Epub ahead of print Apr 17] (PMC in progress).
Y. Akasaki, N. Ouchi, Y. Izumiya, B.L. Bernardo, N.K. Lebrasseur, K. Walsh (2013). Glycolytic fast-twitch muscle fiber restoration counters adverse age-related changes in body composition and metabolism. Aging Cell. 13:80-91 (PMC3947044). J.L. Parker-Duffen, K. Nakamura, M. Silver, R. Kikuchi, U. Tigges, S. Yoshida, M.S. Denzel, B. Ranscht, K. Walsh (2013). T-cadherin is essential for adiponectin-mediated revascularization. J Biol Chem. 288:24886-97 (PMC3750183). I. Shiojima, S. Schiekofer, J.G. Schneider, K. Belisle, K. Sato, M. Andrassy, G. Galasso, K. Walsh (2012). Short-term akt activation in cardiac muscle cells improves contractile function in failing hearts. Am J Pathol. 181:1969-76 (PMC3509766). M. Shimano, N. Ouchi, K. Walsh (2012). Cardiokines: recent progress in elucidating the cardiac secretome. Circulation. 126:e327-32 (PMC not applicable). K.N. Papanicolaou, R. Kikuchi, G.A. Ngoh, K.A. Coughlan, I. Dominguez, W.C. Stanley, K. Walsh (2012). Mitofusins 1 and 2 are essential for postnatal metabolic remodeling in heart. Circ Res. 111(8):1012-26 (PMC3518037). K.N. Papanicolaou, M.M. Phillippo, K. Walsh (2012). Mitofusins and the mitochondrial permeability transition: the potential downside of mitochondrial fusion. Am J Physiol Heart Circ Physiol. 303(3):H243-55. (PMC3423162). G.A. Ngoh, K.N. Papanicolaou, K. Walsh (2012). Loss of mitofusin 2 promotes endoplasmic reticulum stress. J Biol Chem. 287:20321-32 (PMC3370214). K.N. Papanicolaou, G. Ngoh, E.R. Dabkowski, K.A. O’Connell, R.F. Ribeiro, W.C. Stanley, K. Walsh (2012). Cardiomyocyte deletion of mitofusin-1 leads to mitochondrial fragmentation and improves tolerance to ROS-induced mitochondrial dysfunction and cell death. Am J Physiol Heart Circ Physiol. 302:H167-79 (PMC3334239). M. Shimano, N. Ouchi, K. Nakamura, B. van Wijk, K. Ohashi, Y. Asaumi, A. Higuchi, D.R. Pimentel, F. Sam, T. Murohara, M.J. van den Hoff, K. Walsh (2011). Cardiac myocyte follistatin-like 1 functions to attenuate hypertrophy following pressure overload. Proc Natl Acad Sci USA. 108:E899-906 (PMC3203781). A. El-Armouche, N. Ouchi, K. Tanaka, G. Doros, K. Wittköpper, T. Schulze, T. Eschenhagen, K. Walsh, F. Sam (2011). Follistatin-like 1 in chronic systolic heart failure – a marker of left ventricular remodeling. Circ Heart Fail. 4:621-7 (PMC3178753). K.N. Papanicolaou, R.J. Khairallah, G.A. Ngoh, A. Chikando, I. Luptak, K.M. O’Shea, D.D. Riley, J.J. Lugus, W.S. Colucci, W.J. Lederer, W.C. Stanley, K. Walsh (2011). Mitofusin-2 maintains mitochondrial structure and contributes to stress-induced permeability transition in cardiac myocytes. Mol Cell Biol. 31:1309-28 (PMC3067905). M. Shimano, N. Ouchi, K. Nakamura, Y. Oshima, A. Higuchi, D.R. Pimentel, K.D. Panse, E. Lara-Pezzi, S.J. Lee, F. Sam, K. Walsh (2011). Cardiac myocyte-specific ablation of Follistatin-like 3 attenuates stress-induced myocardial hypertrophy. J Biol Chem. 286:9840-8 (PMC3203781). Editor’s Choice feature in Science Signaling. N. Ouchi, A. Higuchi, K. Ohashi, Y. Oshima, N. Gokce, R. Shibata, Y. Akasaki, A. Shimono, K. Walsh (2010). Sfrp5 Is an anti-inflammatory adipokine that modulates metabolic dysfunction in obesity. Science. 329:454-7. Accompanied by editorial (PMC3132938). K. Ohashi, N. Ouchi, A. Higuchi, R.J. Shaw, K. Walsh (2010). LKB1-deficiency in Tie2-Cre-expressing cells impairs ischemia-induced angiogenesis. J Biol Chem. 285:22291-8 (PMC2903404). N. Ouchi, Y. Asaumi, K. Ohashi, A. Higuchi, S. Sono-Romanelli, Y. Oshima, K. Walsh (2010) DIP2A functions as a FSTL1 receptor. J Biol Chem. 285:7127-34 (PMC2844162). K. Ohashi, J.L. Parker, N. Ouchi, A. Higuchi, J.A. Vita, N. Gokce, A.A. Pedersen, C. Kalthoff, S. Tullin, A. Sams, R. Summer, K. Walsh (2010). Adiponectin promotes macrophage polarization toward an anti-inflammatory phenotype. J Biol Chem. 285:6153-60 (PMC2825410). Y. Ikeda, K. Sato, D.R. Pimental, F. Sam, R.J. Shaw, J.R. Dyck, K. Walsh (2009). Cardiac-specific deletion of LKB1 leads to hypertrophy and dysfunction. J. Biol. Chem. 284:35839-35849 (PMC2791013). Y. Oshima, N. Ouchi, M. Shimano, D.R. Pimentel,K.N. Papanicolaou, K.D. Panse, K. Tsuchida, E. Lara-Pezzi, S.J. Lee, K. Walsh (2009). Activin A and follistatin-like 3 determine the susceptibility of heart to ischemic injury. Circulation. 120:1606-15 (PMC2764796). A. Higuchi, K. Ohashi, S. Kihara, K. Walsh, N. Ouchi (2009). Adiponectin suppresses pathological microvessel formation in retina through modulation of tumor necrosis factor-? expression. Circ Res. 104:1058-65 (PMC2740643). C.Y. Wang, H.H. Kim, Y. Hiroi, N. Sawada, S. Salomone, L.E. Benjamin, K. Walsh, M.A. Moskowitz, J.K. Liao (2009). Obesity increases vascular senescence andsusceptibility to ischemic injury through chronic activation of Akt and mTOR. Science Signal. 2:ra11 (PMC2667954). A.K. Peter, C.Y. Ko, M.H. Kim, N. Hsu, N. Ouchi, S. Rhie, Y. Izumiya, L. Zeng, K. Walsh, R.H. Crosbie (2009). Myogenic Akt signaling upregulates the utrophin-glycoprotein complex and promotes sarcolemma stability in muscular dystrophy. Hum Mol Genet. 18:318-27 (PMC2638781). N. Ouchi, Y. Oshima, K. Ohashi, A. Higuchi, C. Ikegami, Y. Izumiya, K. Walsh (2008). Follistatin-like 1, a secreted muscle protein, promotes endothelialcell function and revascularization in ischemic tissue through a nitric oxide synthesis-dependent mechanism. J Biol Chem. 283:32802-11 (PMC2583310). Y. Oshima, N. Ouchi, K. Sato, Y. Izumiya, D.R. Pimentel, K. Walsh (2008). Follistatin-like 1 is an Akt-regulated cardioprotective factor that is secreted by the heart. Circulation. 117:3099-3108 (PMC2679251). Y. Izumiya, T. Hopkins, C. Morris, K. Sato, L. Zeng, J. Viereck, J.A. Hamilton, N. Ouchi, N.K. LeBrasseur, K. Walsh (2008). Fast/Glycolytic muscle fiber growth reduces fat mass and improves metabolic parameters in obese mice. Cell Metab. 7:159-72 (PMC2828690). Accompanied by editorial. R. Summer, F.F. Little, N. Ouchi, Y. Takemura, T. Aprahamian, D. Dwyer, K. Fitzsimmons, B. Suki, H. Parameswaran, A. Fine, K. Walsh (2008). Alveolar macrophage activation and an emphysema-like phenotype in adiponectin deficient mice. Am J Physiol Lung Cell Mol Physiol 294:L1035-42 (PMC3575679). Accompanied by editorial. Y. Takemura, N. Ouchi, R. Shibata, T. Aprahamian, M.T. Kirber, R.S. Summer, S. Kihara, K .Walsh (2007). Adiponectin modulatesinflammatory reactions via calreticulin receptor-dependent clearance of early apoptotic bodies. J Clin Invest. 117:375-86 (PMC1770947). T.L. Phung, K. Ziv, D. Dabydeen, G. Eyiah-Mensah, M. Riveros, C. Perruzzi, J. Sun, R.A. Monahan-Earley, I. Shiojima, J.A. Nagy, M.I. Lin, K. Walsh, A.M. Dvorak,D.M. Briscoe, M. Neeman, W.C. Sessa, H.F. Dvorak, L.E. Benjamin (2006). Pathological angiogenesis is induced by sustained Akt signaling and inhibited by rapamycin. Cancer Cell. 10: 159-70 (PMC2531257). Accompanied by editorial.
Shiojima, K. Sato, Y. Izumiya, S. Schiekofer, M. Ito, R. Liao, W.S. Colucci, K. Walsh (2005). Disruption of coordinated cardiac hypertrophy and angiogenesis contributes to the transition to heart failure. J Clin Invest. 115:2108-18 (PMC1180541). Accompanied by editorial. R. Shibata, K. Sato, D.R. Pimentel, Y. Takemura, S. Kihara, K. Ohashi, T. Funahashi, N. Ouchi, K. Walsh (2005). Adiponectin protects against myocardial ischemia-reperfusion injury through AMPK- and COX-2- dependent mechanisms. Nat Med. 10: 1096-103 (PMC2828682). Accompanied by editorial. E. Ackah, J. Yu, S. Zoellner, Y. Iwakiri, C. Skurk, R. Shibata, N. Ouchi, R.M. Easton, G. Galasso, M.J. Birnbaum, K. Walsh, W.C. Sessa (2005).Akt1/protein kinase B? is critical for ischemic and VEGF-mediated angiogenesis. J Clin Invest. 115:2119-27 (PMC1180542). Accompanied by editorial. I. Shiojima, K. Sato, Y. Izumiya, S. Schiekofer, M. Ito, R. Liao, W.S. Colucci, K. Walsh (2005). Disruption of coordinated cardiac hypertrophy and angiogenesis contributes to the transition to heart failure. J Clin Invest. 115:2108-18 (PMC1180541). Accompanied by editorial. C. Skurk, Y. Izumiya, H. Maatz, P. Razeghi, I. Shiojima, M. Sandri, K. Sato, L. Zeng, S. Schiekofer, D. Pimentel, S. Lecker, H. Taegtmeyer, A.L. Goldberg, K. Walsh (2005). The FOXO3a transcription factor regulates cardiac myocyte size downstream of AKT signaling. J Biol Chem. 280:20814-23 (PMC3632436). J.F. Sun, T. Phung, I. Shiojima, T. Felske, J.N. Upalakalin, D. Feng, T. Kornaga, T. Dor, A.M. Dvorak, K. Walsh, L.E. Benjamin (2005). Microvascular patterning is controlled by fine-tuning the Akt signal. Proc Natl Acad Sci USA. 102:128-33 (PMC538747). R. Shibata, N. Ouchi, M. Ito, S. Kihara, I. Shiojima, D.R. Pimentel, M. Kumada, K. Sato, S. Schiekofer, K. Ohashi, T. Funahashi, W.S. Colucci, K. Walsh (2004). Adiponectin-mediated modulation of hypertrophic signals in the heart. Nat Med. 10:1384-89 (PMC2828675). T. Aprahamian, I. Rifkin, B. Hugel, J.-M. Freyssinet, K. Sato, J.J. Castellot, Jr., K. Walsh (2004).Impaired clearance of apoptotic cells promotes synergy between atherogenesis and autoimmune disease. J Exp Med. 199:1121-31 (PMC2211887).
M. Sandri, C. Sandri, A. Gilbert, C. Skurk, E. Calabria, A. Picard, K. Walsh, S. Schiaffino, S.H. Lecker, A.L. Goldberg (2004). Foxo transcription factors induce the atrophy-related ubiquitin ligase atrogin-1 and cause skeletal muscle atrophy. Cell. 117:399-412 (PMC3619734). A. Takahashi, Y. Kureishi, J. Yang, Z. Luo, K. Guo, D. Mukhopadhyay, Y. Ivashchenko, D. Branellec, K. Walsh (2002). Myogenic Akt signaling regulates blood vessel recruitment during myofiber growth. Mol Cell Biol. 22:4803-14 (PMC133891). Y. Kureishi, Z. Luo, I. Shiojima, A. Bialik, D. Fulton, D.J. Lefer, W.C. Sessa, K. Walsh (2000) The HMG-CoA reductase inhibitor simvastatin activates the protein kinase Akt and promotes angiogenesis in normocholesterolemic animals. Nat Med. 6:1004-10 (PMC2828689). Accompanied by editorial. Z. Luo, Y. Fujio, Y. Kureishi, R.D. Rudic, G. Daumerie, D. Fulton, W.C. Sessa, K. Walsh (2000) Acute modulation of endothelial Akt/PKB activity alters nitric oxide-dependent vasomotor activity in vivo. J Clin Invest. 106:493-9 (PMC380252). Y. Fujio, T. Nguyen, D. Wencker, R.N. Kitsis, K. Walsh (2000). Akt promotes survival of cardiomyocytes in vitro and protects against ischemia-reperfusion injury in mouse heart. Circulation. 101:660-7 (PMC3627349). D. Fulton, J.P. Gratton, T. McCabe, J. Fontana, Y. Fujio, K. Walsh, T. Franke, A. Papapetropoulos, W.C. Sessa (1999). Regulation of endothelium-derived nitric oxide production by the protein kinase Akt. Nature. 399:597-601 (PMC3637917). Y. Fujio and K. Walsh (1999). Akt mediates cytoprotection of endothelial cells by vascular endothelial growth factor in an anchorage-dependent manner. J Biol Chem. 274:16349-54 (PMC3624707). M. Sata and K. Walsh (1998). Oxidized LDL activates Fas-mediated endothelial cell apoptosis. J Clin Invest.102:1682-89 (PMC509116). M. Sata and K. Walsh (1998). TNFalpha-regulation of Fas ligand expression on the vascular endothelium modulates leukocyte extravasation. Nat Med. 4:415-20 (PMC2828686). J. Wang and K. Walsh (1996). Resistance to apoptosis conferred by Cdk inhibitors during myocyte differentiation. Science. 273:359-61 (PMC3641673).