Follistatin-like 1 is an Akt-regulated cardioprotective factor that is secreted by the heart
Open accessAbstract
BACKGROUND: The Akt protein kinase is an important mediator of cardiac myocyte growth and survival. To identify factors with novel therapeutic applications in cardiac diseases, we focused on the identification of factors secreted from Akt1-activated cells that have cardioprotective effects through autocrine/paracrine mechanisms. METHODS AND RESULTS: Using an inducible Akt1 transgenic mouse model, we have found that follistatin-like 1 (Fstl1) protein and transcript expression are increased 4.0- and 2.0-fold, respectively, by Akt activation in the heart (P<0.05). Fstl1 transcript was also upregulated in response to myocardial stresses including transverse aortic constriction, ischemia/reperfusion injury, and myocardial infarction. Adenovirus-mediated overexpression of Fstl1 protected cultured neonatal rat ventricular myocytes from hypoxia/reoxygenation-induced apoptosis (P<0.01), and this protective effect was dependent on the upregulation of both Akt and ERK activities. Conversely, knockdown of Fstl1 in cardiac myocytes decreased basal Akt signaling and increased the frequency of apoptotic death in vitro (P<0.01). The intravenous administration of an adenoviral encoding Fstl1 to mice resulted in a 66.0% reduction in myocardial infarct size after ischemia/reperfusion injury that was accompanied by a 70.9% reduction in apoptosis in the heart (P<0.01). CONCLUSIONS: These results indicate that Fstl1 is a cardiac-secreted factor that functions as an antiapoptotic protein. Fstl1 could play a role in myocardial maintenance and repair in response to harmful stimuli.
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FSTL1 has cardioprotective effects in animal models of cardiac injury, promoting endothelial cell function and revascularization through a mechanism that includes nitric oxide synthase.
“FSTL1 has been shown to possess cardioprotective effects, promoting endothelial cell function and thereby revascularization in animal models of cardiac injury through a mechanism that includes nitric oxide synthase (194, 195).”
From Muscle–Organ Crosstalk: The Emerging Roles of Myokines (2020) · cites this paper as [195]
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1 retracted
Das, S., Fraga, C. G., & Das, D. K. (2006) · Free Radical Research · doi:10.1080/10715760600833085 · Cited by 112 · see citing works
Retractedde Bold, A. J., Borenstein, H., Veress, A. T., & Sonnenberg, H. (1981) · Life Sciences · doi:10.1016/0024-3205(81)90370-2 · Cited by 3,144 · see citing works
Gnecchi, M., He, H., Liang, O. D., Melo, L. G., Morello, F., Mu, H., Noiseux, N., Zhang, L., Pratt, R. E., Ingwall, J. S., et al. (2005) · Nature Medicine · doi:10.1038/nm0405-367 · Cited by 1,677 · see citing works
Shiojima, I. (2005) · Journal of Clinical Investigation · doi:10.1172/jci24682 · Cited by 939 · see citing works
Colucci, W. S., Elkayam, U., Horton, D. P., Abraham, W. T., Bourge, R. C., Johnson, A. D., Wagoner, L. E., Givertz, M. M., Liang, C., Neibaur, M., et al. (2000) · New England Journal of Medicine · doi:10.1056/nejm200007273430403 · Cited by 907 · see citing works
Fujio, Y., Nguyen, T. U., Wencker, D., Kitsis, R. N., & Walsh, K. (2000) · Circulation · doi:10.1161/01.cir.101.6.660 · Cited by 846 · see citing works
Self-citationThe MEK1–ERK1/2 signaling pathway promotes compensated cardiac hypertrophy in transgenic mice
Bueno, O. F., Windt, L. J. D., Tymitz, K. M., Witt, S. A., Kimball, T. R., Klevitsky, R., Hewett, T. E., Jones, S. P., Lefer, D. J., Peng, C., et al. (2000) · The EMBO Journal · doi:10.1093/emboj/19.23.6341 · Cited by 774 · see citing works
The amino acid sequence of an atrial peptide with potent diuretic and natriuretic properties
Flynn, T. G., de Bold, M. L. K., & de Bold, A. J. (1983) · Biochemical and Biophysical Research Communications · doi:10.1016/0006-291x(83)91675-3 · Cited by 739 · see citing works
Kempf, T., Eden, M., Strelau, J., Naguib, M., Willenbockel, C., Tongers, J., Heineke, J., Kotlarz, D., Xu, J., Molkentin, J. D., et al. (2006) · Circulation Research · doi:10.1161/01.res.0000202805.73038.48 · Cited by 651 · see citing works
Extracellular Regulation of BMP Signaling in Vertebrates: A Cocktail of Modulators
Balemans, W., & Hul, W. V. (2002) · Developmental Biology · doi:10.1006/dbio.2002.0779 · Cited by 616 · see citing works
Xu, J., Kimball, T. R., Lorenz, J. N., Brown, D. A., Bauskin, A. R., Klevitsky, R., Hewett, T. E., Breit, S. N., & Molkentin, J. D. (2006) · Circulation Research · doi:10.1161/01.res.0000202804.84885.d0 · Cited by 507 · see citing works
Prognostic Utility of Growth Differentiation Factor-15 in Patients With Chronic Heart Failure
Kempf, T., von Haehling, S., Peter, T., Allhoff, T., Cicoira, M., Doehner, W., Ponikowski, P. P., Filippatos, G. S., Rozentryt, P., Drexler, H., et al. (2007) · Journal of the American College of Cardiology · doi:10.1016/j.jacc.2007.04.091 · Cited by 492 · see citing works
Akt induces enhanced myocardial contractility and cell size in vivo in transgenic mice
Condorelli, G., Drusco, A., Stassi, G., Bellacosa, A., Roncarati, R., Iaccarino, G., Russo, M. A., Gu, Y., Dalton, N. D., Chung, C., et al. (2002) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.172376399 · Cited by 461 · see citing works
Phenotypic Spectrum Caused by Transgenic Overexpression of Activated Akt in the Heart
Matsui, T., Li, L., Wu, J. C., Cook, S. A., Nagoshi, T., Picard, M. H., Liao, R., & Rosenzweig, A. (2002) · Journal of Biological Chemistry · doi:10.1074/jbc.m200347200 · Cited by 434 · see citing works
Yue, T., Wang, C., Gu, J.-L., Ma, X., Kumar, S., Lee, J. C., Feuerstein, G., Thomas, H. C., Maleeff, B. E., & Ohlstein, E. H. (2000) · Circulation Research · doi:10.1161/01.res.86.6.692 · Cited by 421 · see citing works
Liu, T., Qian, W., Gritsenko, M. A., Camp, D., Monroe, M. E., Moore, R. J., & Smith, R. D. (2005) · Journal of Proteome Research · doi:10.1021/pr0502065 · Cited by 406 · see citing works
Wollert, K. C., Kempf, T., Peter, T., Olofsson, S., James, S. K., Johnston, N., Lindahl, B., Horn-Wichmann, R., Brabant, G. E., Simoons, M. L., et al. (2007) · Circulation · doi:10.1161/circulationaha.106.650846 · Cited by 379 · see citing works
Regulation of cardiac growth and coronary angiogenesis by the Akt/PKB signaling pathwayPreprint
Shiojima, I., & Walsh, K. X. (2006) · Genes & Development · doi:10.1101/gad.1492806 · Cited by 355 · see citing works
Self-citationIzumiya, Y., Shiojima, I., Sato, K., Sawyer, D. B., Colucci, W. S., & Walsh, K. X. (2006) · Hypertension · doi:10.1161/01.hyp.0000215207.54689.31 · Cited by 324 · see citing works
Self-citationTang, W. H. W., Francis, G. S., Morrow, D. A., Newby, L. K., Cannon, C. P., Jesse, R. L., Storrow, A. B., Christenson, R. H., Christenson, R. H., Apple, F. S., et al. (2007) · Circulation · doi:10.1161/circulationaha.107.185267 · Cited by 311 · see citing works
Cloning and sequence analysis of cDNA encoding a precursor for human brain natriuretic peptide
Sudoh, T., Maekawa, K., Kojima, M., et al. (1989) · Biochemical and Biophysical Research Communications · doi:10.1016/0006-291x(89)92269-9 · Cited by 271 · see citing works
Cai, Z., Zhong, H., Bosch‐Marcé, M., Fox-Talbot, K., Wang, L., Wei, C., Trush, M. A., & Semenza, G. L. (2007) · Cardiovascular Research · doi:10.1093/cvr/cvm035 · Cited by 244 · see citing works
Pim-1 regulates cardiomyocyte survival downstream of Akt
Muraski, J. A., Rota, M., Misao, Y., Fransioli, J., Cottage, C. T., Gude, N. A., Esposito, G., Delucchi, F., Arcarese, M. L., Alvarez, R., et al. (2007) · Nature Medicine · doi:10.1038/nm1671 · Cited by 239 · see citing works
Nuclear Targeting of Akt Enhances Kinase Activity and Survival of Cardiomyocytes
Shiraishi, I., Melendez, J., Ahn, Y., Skavdahl, M., Murphy, E., Welch, S., Schaefer, E., Walsh, K., Rosenzweig, A., Torella, D., et al. (2004) · Circulation Research · doi:10.1161/01.res.0000124394.01180.be · Cited by 212 · see citing works
Self-citationDeBold, J. F., Borenstein, H., At, V., et al. (2001) · PubMed · doi:10.1681/asn.v122403 · Cited by 191 · see citing works
Adrenomedullin: A Possible Autocrine or Paracrine Inhibitor of Hypertrophy of Cardiomyocytes
Tsuruda, T., Kato, J., Kitamura, K., Kuwasako, K., Imamura, T., Koiwaya, Y., Tsuji, T., Kangawa, K., & Eto, T. (1998) · Hypertension · doi:10.1161/01.hyp.31.1.505 · Cited by 169 · see citing works
Myostatin Regulates Cardiomyocyte Growth Through Modulation of Akt Signaling
Morissette, M. R., Cook, S. A., Foo, S., McKoy, G., Ashida, N., Novikov, M., Scherrer‐Crosbie, M., Li, L., Matsui, T., Brooks, G., et al. (2006) · Circulation Research · doi:10.1161/01.res.0000231290.45676.d4 · Cited by 153 · see citing works
Miao, W., Luo, Z., Kitsis, R. N., & Walsh, K. (2000) · Journal of Molecular and Cellular Cardiology · doi:10.1006/jmcc.2000.1283 · Cited by 143 · see citing works
Self-citationNuclear Targeting of Akt Enhances Ventricular Function and Myocyte Contractility
Rota, M., Boni, A., Urbanek, K., Padín-Iruegas, E., Kajstura, T. J., Fiore, G., Kubo, H., Sonnenblick, E. H., Musso, E., Houser, S. R., et al. (2005) · Circulation Research · doi:10.1161/01.res.0000196568.11624.ae · Cited by 133 · see citing works
Taniyama, Y., & Walsh, K. (2002) · Journal of Molecular and Cellular Cardiology · doi:10.1006/jmcc.2002.2068 · Cited by 100 · see citing works
Self-citationAkt3 overexpression in the heart results in progression from adaptive to maladaptive hypertrophy
Taniyama, Y., Ito, M., Sato, K., et al. (2005) · Journal of Molecular and Cellular Cardiology · doi:10.1016/j.yjmcc.2004.12.002 · Cited by 99 · see citing works
Self-citationIzumi, M., Fujio, Y., Kunisada, K., et al. (2001) · Journal of Biological Chemistry · doi:10.1074/jbc.m101463200 · Cited by 95 · see citing works
Shibata, R., Sato, K., Kumada, M., Izumiya, Y., Sonoda, M., Kihara, S., Ouchi, N., & Walsh, K. X. (2007) · Cardiovascular Research · doi:10.1016/j.cardiores.2007.02.010 · Cited by 92 · see citing works
Self-citationMyostatin does not regulate cardiac hypertrophy or fibrosis
Cohn, R. D., Liang, H.-Y., Shetty, R., Abraham, T. P., & Wagner, K. R. (2007) · Neuromuscular Disorders · doi:10.1016/j.nmd.2007.01.011 · Cited by 88 · see citing works
Sumitomo, K., Kurisaki, A., Yamakawa, N., Tsuchida, K., Shimizu, E., Sone, S., & Sugino, H. (2000) · Cancer Letters · doi:10.1016/s0304-3835(00)00407-9 · Cited by 74 · see citing works
Johnston, I., Spence, H. J., Winnie, J. N., McGarry, L., Vass, J. K., Meagher, L., Stapleton, G., & Ozanne, B. W. (2000) · Oncogene · doi:10.1038/sj.onc.1203927 · Cited by 69 · see citing works
Cloning and sequence analysis of cDNA encoding a precursor for porcine brain natriuretic peptide
Maekawa, K., Sudoh, T., Furusawa, M., et al. (1988) · Biochemical and Biophysical Research Communications · doi:10.1016/s0006-291x(88)80062-7 · Cited by 65 · see citing works
Frost, R. J., & Engelhardt, S. H. (2007) · Circulation · doi:10.1161/circulationaha.107.696468 · Cited by 59 · see citing works
Mashimo, J., Maniwa, R., Sugino, H., & Nose, K. (1997) · Cancer Letters · doi:10.1016/s0304-3835(97)04700-9 · Cited by 59 · see citing works
Artaza, J. N., Reisz‐Porszasz, S., Dow, J., Kloner, R. A., Tsao, J., Bhasin, S., & González-Cadavid, N. F. (2007) · Journal of Endocrinology · doi:10.1677/joe-07-0072 · Cited by 56 · see citing works
Funamoto, M., Hishinuma, S., Fujio, Y., Matsuda, Y., Kunisada, K., Oh, H., Negoro, S., Tone, E., Kishimoto, T., & Yamauchi‐Takihara, K. (2000) · Journal of Molecular and Cellular Cardiology · doi:10.1006/jmcc.2000.1161 · Cited by 53 · see citing works
Schiekofer, S., Shiojima, I., Sato, K., Galasso, G., Oshima, Y., & Walsh, K. (2006) · Physiological Genomics · doi:10.1152/physiolgenomics.00234.2005 · Cited by 53 · see citing works
Self-citationMcKoy, G., Bicknell, K. A., Patel, K., & BROOKS, G. (2007) · Cardiovascular Research · doi:10.1016/j.cardiores.2007.02.023 · Cited by 49 · see citing works
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Pedersen, B. K., & Febbraio, M. A. (2012) · Nature Reviews Endocrinology · doi:10.1038/nrendo.2012.49 · Cited by 2,909 · see citing works
Muscle–Organ Crosstalk: The Emerging Roles of Myokines
Severinsen, M. C. K., & Pedersen, B. K. (2020) · Endocrine Reviews · doi:10.1210/endrev/bnaa016 · Cited by 1,226 · see citing works
“FSTL1 has been shown to possess cardioprotective effects, promoting endothelial cell function and thereby revascularization in animal models of cardiac injury through a mechanism that includes nitric oxide synthase (194, 195).”
BackgroundPedersen, B. K. (2013) · Comprehensive physiology · doi:10.1002/cphy.c120033 · Cited by 516 · see citing works
Ouchi, N., Oshima, Y., Ohashi, K., Higuchi, A., Ikegami, C., Izumiya, Y., & Walsh, K. (2008) · Journal of Biological Chemistry · doi:10.1074/jbc.m803440200 · Cited by 338 · see citing works
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Priest, C., & Tontonoz, P. (2019) · Nature Metabolism · doi:10.1038/s42255-019-0145-5 · Cited by 279 · see citing works
Recinella, L., Orlando, G., Ferrante, C., Chiavaroli, A., Brunetti, L., & Leone, S. (2020) · Frontiers in Physiology · doi:10.3389/fphys.2020.578966 · Cited by 261 · see citing works
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Ogura, Y., Ouchi, N., Ohashi, K., Shibata, R., Kataoka, Y., Kambara, T., Kito, T., Maruyama, S., Yuasa, D., Matsuo, K., et al. (2012) · Circulation · doi:10.1161/circulationaha.112.115089 · Cited by 183 · see citing works
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Shimano, M., Ouchi, N., & Walsh, K. (2012) · Circulation · doi:10.1161/circulationaha.112.150656 · Cited by 116 · see citing works
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Seki, M., Powers, J. C., Maruyama, S., Zuriaga, M. A., Wu, C.-L., Kurishima, C., Kim, L., Johnson, J., Poidomani, A., Wang, T., et al. (2018) · Circulation Heart Failure · doi:10.1161/circheartfailure.117.004486 · Cited by 59 · see citing works
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- Authors
- Oshima, Y., Ouchi, N., Sato, K., Izumiya, Y., Pimentel, D. R., & Walsh, K.
- Affiliations
- Boston University (US)
- Venue
- Circulation
- Published
- 2008-06-17
- Volume
- 117
- Issue
- 24
- Pages
- 3099-3108
- ISSN
- 0009-7322 (ISSN-L)
- 1524-4539
- PMC
- PMC2679251
- OpenAlex
- W2121202595
- Cited by
- 275
- References
- 43
- Citations by year
- 2026: 8 · 2025: 23 · 2024: 12 · 2023: 9 · 2022: 20 · 2021: 15 · 2020: 28 · 2019: 18 · 2018: 13 · 2017: 18 · 2016: 21 · 2015: 15 · 2014: 15 · 2013: 11 · 2012: 11
- FWCI
- 8.99
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Circulation (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institute on Aging (R01AG015052, R37AG015052, AG15052)
- National Heart, Lung, and Blood Institute (HL81587, HL77774, R01HL086785, HL71563, R01HL116591, P01HL081587, HL 86785, R01HL077774, K08HL071563)
- Topics
- Health Sciences › Medicine › Pathology and Forensic Medicine › Cardiac Ischemia and Reperfusion
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiac Fibrosis and Remodeling
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cell death mechanisms and regulation
- Keywords
- FSTL1, Akt signaling, cardioprotection, myocardial infarction, ischemia-reperfusion injury, apoptosis, ERK signaling, autocrine and paracrine signaling, ventricular myocytes, transverse aortic constriction, adenoviral gene transfer
- MeSH terms
- Animals, Cardiotonic Agents, Cloning, Molecular, Gene Expression Regulation, Heart, Humans, Major Histocompatibility Complex, Mice, Transgenic, Transcription, Genetic, Reperfusion Injury, Up-Regulation, DNA, Complementary, Oligonucleotide Array Sequence Analysis, Myocytes, Cardiac, RNA, Small Interfering, Follistatin-Related Proteins, Proto-Oncogene Proteins c-akt, Mice, Rats
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