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. Many of these studies involve analyses of the PI3-kinase/Akt/GSK/Forkhead signaling axis. This pathway is of critical importance in the regulation of organ growth and body size. 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/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. To a varying degree, metabolic disorders afflict 2 of every 3 Americans and they represent a rapidly-growing threat to the health worldwide, due in large part to an increase in the prevalence of cardiovascular diseases. 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 this laboratory identified Sfrp5 as a new anti-inflammatory adipokine, and demonstrated that it functions to control systemic metabolism through regulation of non-canonical Wnt signaling in adipose tissue. 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 311 publications as of April 2012)
Nakamura K, Fuster JJ, Walsh K. Adipokines: A link between obesity and
cardiovascular disease. J Cardiol. 2013 Dec 16. pii: S0914-5087(13)00355-9.doi:10.1016/j.jjcc.2013.11.006. [Epub ahead of print] PubMed PMID: 24355497.
Akasaki Y, Ouchi N, Izumiya Y, Bernardo BL, Lebrasseur NK, Walsh K. Glycolytic fast-twitch muscle fiber restoration counters adverse age-related changes in body composition and metabolism. Aging Cell. 2013 Aug 23. doi: 10.1111/acel.12153. [Epub ahead of print] PubMed PMID: 24033924.
Parker-Duffen JL, Nakamura K, Silver M, Kikuchi R, Tigges U, Yoshida S, Denzel MS, Ranscht B, Walsh K. T-cadherin is essential for adiponectin-mediated revascularization. J Biol Chem. 2013 Aug 23;288(34):24886-97. doi:
10.1074/jbc.M113.454835. Epub 2013 Jul 3. PubMed PMID: 23824191; PubMed Central PMCID: PMC3750183.
Shiojima I, Schiekofer S, Schneider JG, Belisle K, Sato K, Andrassy M, Galasso
G, Walsh K. Short-term akt activation in cardiac muscle cells improves
contractile function in failing hearts. Am J Pathol. 2012 Dec;181(6):1969-76.
doi: 10.1016/j.ajpath.2012.08.020. Epub 2012 Sep 30. PubMed PMID: 23031259; PubMed Central PMCID: PMC3509766.
Shimano M, Ouchi N, Walsh K. Cardiokines: recent progress in elucidating the
cardiac secretome. Circulation. 2012 Nov 20;126(21):e327-32. doi:
10.1161/CIRCULATIONAHA.112.150656. Review. PubMed PMID: 23169257.
Papanicolaou KN, Kikuchi R, Ngoh GA, Coughlan KA, Dominguez I, Stanley WC, Walsh K. Mitofusins 1 and 2 are essential for postnatal metabolic remodeling in heart. Circ Res. 2012 Sep 28;111(8):1012-26. Epub 2012 Aug 17. PubMed PMID: 22904094; PubMed Central PMCID: PMC3518037.
Papanicolaou KN, Phillippo MM, Walsh K. Mitofusins and the mitochondrial
permeability transition: the potential downside of mitochondrial fusion. Am J
Physiol Heart Circ Physiol. 2012 Aug 1;303(3):H243-55. doi: 10.1152/ajpheart.00185.2012. Epub 2012 May 25. Review. PubMed PMID: 22636681; PubMed Central PMCID: PMC3423162.
G. A. Ngoh, K. N. Papanicolaou, K. Walsh (2012). Loss of mitofusin 2
promotes endoplasmic reticulum stress. J. Biol. Chem. 287:20321-20332.
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. In press.
K. N. Papanicolaou, G. Ngoh, E. R. Dabkowski, K. A. O’Connell, R. F. Ribeiro, W. C. Stanley, K. Walsh (2012). Cardiomyocyte targeted deletion of mitofusin-1 leads to formation of smaller mitochondria and improves tolerance to reactive oxygen species-induced mitochondrial dysfunction and cell death. Am. J. Physiol. Heart Circ. Physiol. 302:H167-H179 (PMC in progress).
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-E906
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. [Epub ahead of print May 25].
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. 4:621-277 (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. 31:1309-1328 (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. 286:9840-9848 (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. 329:454-457. 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. 285:22291-22298 (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. 285:7127-7134 (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. 285:6153-6160 (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. 120:1606-1615 (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. 104:1058-1065 (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. 18:318-327 (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. 283:32802-32811 (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 musclefiber growth reduces fat mass and improves metabolic parameters in obese mice. Cell Metab. 7:159-172. Accompanied by editorial (PMC2828690).
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-L1042 . 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. 117:375-386 (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: 159-170 (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. 115:2108-2118 (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: 1096-1103 (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. 115:2119-2127 (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. 115:2108-2118 (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. 280:20814-20823.
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. 102:128-133 (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. 10:1384-1389 (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. 199:1121-1131 (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.
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. 22:4803-4814 (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. 6:1004-1010. Accompanied by editorial (PMC2828689).
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. 106:493-499 (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. 101:660-667.
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.
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. 274:16349-16354.
M. Sata and K. Walsh (1998). Oxidized LDL activates Fas-mediated endothelial cell apoptosis. J. Clin. Invest.102:1682-1689.
M. Sata and K. Walsh (1998). TNF?-regulation of Fas ligand expression on the vascular endothelium modulates leukocyte extravasation. Nat. Med. 4:415-420.
J. Wang and K. Walsh (1996). Resistance to apoptosis conferred by Cdk inhibitors during myocyte differentiation. Science 273:359-361.