DOI: 10.1161/01.res.82.6.666. Angiotensin II Activates RhoA in Cardiac Myocytes

Angiotensin II Activates RhoA in Cardiac Myocytes

10.1161/01.res.82.6.666

Crossref journal-article

Ovid Technologies (Wolters Kluwer Health)

Circulation Research (276)

Abstract

Abstract —The organization of actin into striated fibers (myofibrils) is one of the major features of cardiac hypertrophy. However, its signal transduction mechanism is not well understood. Although Rho-family small G proteins have been implicated in actin organization in many cell types, it is not fully elucidated whether Rho mediates the organization of actin fibers by hypertrophic stimuli in cardiac myocytes. Therefore, we examined (1) whether Rho is activated by the hypertrophic stimulus, angiotensin II (Ang II), and (2) whether Rho mediates the Ang II–induced organization of actin fibers in cultured neonatal rat cardiac myocytes. Treatment of myocytes with Ang II caused a rapid formation of both striated (mature myofibrils) and nonstriated (premyofibrils) actin fibers within 30 minutes, as determined by phalloidin stainings of the polymerized actin and troponin T stainings. Immunoblot analyses and immunostainings have indicated that cardiac myocytes express RhoA, but RhoB is undetectable. In the control state, RhoA was observed predominantly in the cytosolic fraction, but it was translocated in part to the particulate fraction in response to Ang II, consistent with activation of RhoA by Ang II. Incubation of myocytes with exoenzyme C3 for 48 hours completely ADP-ribosylated Rho in vivo. The C3 treatment abolished formation of premyofibrils induced by Ang II, suggesting that Ang II causes premyofibril formation via a Rho-dependent mechanism. The Ang II–induced mature myofibril formation was only partly abolished by C3. Expression of constitutively active RhoA (V14RhoA) caused the formation of premyofibrils but not mature myofibrils. The C3 treatment inhibited Ang II–induced atrial natriuretic factor induction, whereas it had no effect on c- fos induction. These results indicate that RhoA is activated by Ang II and mediates the Ang II–induced formation of premyofibrils and induction of a subset of genes. Distinct signaling mechanisms seem to be responsible for striated mature myofibril formation by Ang II.

Bibliography

Aoki, H., Izumo, S., & Sadoshima, J. (1998). Angiotensin II Activates RhoA in Cardiac Myocytes. Circulation Research, 82(6), 666â676.

Authors 3

Hiroki Aoki (first)
Seigo Izumo (additional)
Junichi Sadoshima (additional)

References 62 Referenced 170

10.1126/science.2116664
10.1016/S0955-0674(97)80156-1
10.1016/0092-8674(92)90163-7
10.1016/0092-8674(92)90164-8
10.1016/0092-8674(95)90370-4
10.1126/science.275.5304.1308
10.1146/annurev.ph.55.030193.000453
10.1146/annurev.ph.51.030189.001201
10.1146/annurev.ph.55.030193.000415
10.1146/annurev.ph.53.030191.001143
10.1146/annurev.physiol.59.1.551
Sadoshima J, Xu Y, Slayter HS, Izumo S. Autocrine release of angiotensin II mediates stretch-induced hypertrophy of cardiac myocytes in vitro. Cell. 1993;75:977–984. / in vitro. Cell (1993)
10.1161/res.77.2.258
10.1146/annurev.ph.54.030192.001303
10.1161/res.73.3.8348686
10.1161/res.73.3.8348687
Aoki H Sadoshima J Izumo S. The role of mitogen-activated protein kinases in angiotensin II-induced cardiac hypertrophic responses in neonatal rat cardiac myocytes in vitro [abstract]. Circulation. 1996;94(suppl I):I-552.
10.1161/res.77.6.1040
10.1083/jcb.99.6.2268
10.1002/cm.970280102
10.1083/jcb.117.5.1007
10.1073/pnas.94.17.9493
Takaishi K, Sasaki T, Kato M, Yamochi W, Kuroda S, Nakamura T, Takeichi M, Takai Y. Involvement of Rho p21 small GTP-binding protein and its regulator in the HGF-induced cell motility. Oncogene. 1994;9:273–279. / Oncogene (1994)
10.1074/jbc.272.10.6136
10.1016/0922-4106(95)90012-8
10.1016/0014-5793(94)01148-6
10.1016/S0021-9258(19)50052-7
Morii N Narumiya S. Preparation of native and recombinant Clostridium botulinum C3 ADP-ribosyltransferase and identification of Rho proteins by ADP-ribosylation. In: Balch WE Der CJ Hall A eds. Methods in Enzymology. San Diego Calif: Academic Press Inc; 1995;256:196–206. (10.1016/0076-6879(95)56024-6)
10.1002/j.1460-2075.1995.tb00186.x
10.1016/S0092-8674(05)80020-0
10.1016/S0021-9258(18)31748-4
10.1083/jcb.119.3.617
10.1016/S0021-9258(19)50014-X
10.1016/S0021-9258(18)81834-8
10.1083/jcb.111.3.1001
Aktories K Just I. In vitro ADP-ribosylation of Rho by bacterial ADP-ribosyltransferases. In: Balch WE Der CJ Hall A eds. Methods in Enzymology. San Diego Calif: Academic Press Inc; 1995;256:184–195. (10.1016/0076-6879(95)56023-8)
Wiegers W, Just I, Muller H, Hellwig A, Traub P, Aktories K. Alteration of the cytoskeleton of mammalian cells cultured in vitro by Clostridium botulinum C2 toxin and C3 ADP-ribosyltransferase. Eur J Cell Biol. 1991;54:237–245. / Eur J Cell Biol (1991)
10.1074/jbc.271.49.31185
10.1016/S0021-9258(19)74497-4
10.1074/jbc.271.42.25731
10.1002/j.1460-2075.1996.tb00383.x
10.1074/jbc.272.16.10704
10.1074/jbc.271.51.33067
Takaishi K, Sasaki T, Kameyama T, Tsukita S, Tsukita S, Takai Y. Translocation of activated Rho from the cytoplasm to membrane ruffling area, cell-cell adhesion sites and cleavage furrows. Oncogene. 1995;11:39–48. / Oncogene (1995)
10.1242/jcs.108.1.225
10.1161/01.RES.76.1.1
10.1002/j.1460-2075.1996.tb00413.x
10.1161/res.77.6.1053
10.1161/res.80.5.607
10.1074/jbc.270.16.9031
10.1074/jbc.271.44.27374
10.1002/(SICI)1097-4644(19970701)66:1<43::AID-JCB6>3.0.CO;2-Y
10.1093/emboj/16.8.1888
10.1091/mbc.8.4.705
10.1073/pnas.85.2.482
10.1016/S0960-9822(96)00749-X
10.1161/01.RES.80.3.383
10.1083/jcb.139.1.115
10.1242/jcs.109.5.1133
10.1016/S0955-0674(96)80059-7
10.1042/bj3100741
10.1161/res.81.5.672

Dates

Type	When
Created	13 years, 2 months ago (June 11, 2012, 8:47 p.m.)
Deposited	1 year, 3 months ago (May 12, 2024, 4:46 p.m.)
Indexed	2 months ago (July 2, 2025, 2:34 p.m.)
Issued	27 years, 5 months ago (April 6, 1998)
Published	27 years, 5 months ago (April 6, 1998)
Published Print	27 years, 5 months ago (April 6, 1998)

Funders 0

None

BibTeX

@article{Aoki_1998, title={Angiotensin II Activates RhoA in Cardiac Myocytes: A Critical Role of RhoA in Angiotensin II–Induced Premyofibril Formation}, volume={82}, ISSN={1524-4571}, url={http://dx.doi.org/10.1161/01.res.82.6.666}, DOI={10.1161/01.res.82.6.666}, number={6}, journal={Circulation Research}, publisher={Ovid Technologies (Wolters Kluwer Health)}, author={Aoki, Hiroki and Izumo, Seigo and Sadoshima, Junichi}, year={1998}, month=apr, pages={666–676} }

JSON

{
  "indexed": {
    "date-parts": [
      [
        2025,
        7,
        2
      ]
    ],
    "date-time": "2025-07-02T18:34:42Z",
    "timestamp": 1751481282933
  },
  "reference-count": 62,
  "publisher": "Ovid Technologies (Wolters Kluwer Health)",
  "issue": "6",
  "content-domain": {
    "domain": [
      "www.ahajournals.org"
    ],
    "crossmark-restriction": true
  },
  "published-print": {
    "date-parts": [
      [
        1998,
        4,
        6
      ]
    ]
  },
  "abstract": "<jats:p>\n            <jats:italic>Abstract</jats:italic>\n            \u2014The organization of actin into striated fibers (myofibrils) is one of the major features of cardiac hypertrophy. However, its signal transduction mechanism is not well understood. Although Rho-family small G proteins have been implicated in actin organization in many cell types, it is not fully elucidated whether Rho mediates the organization of actin fibers by hypertrophic stimuli in cardiac myocytes. Therefore, we examined (1) whether Rho is activated by the hypertrophic stimulus, angiotensin II (Ang II), and (2) whether Rho mediates the Ang II\u2013induced organization of actin fibers in cultured neonatal rat cardiac myocytes. Treatment of myocytes with Ang II caused a rapid formation of both striated (mature myofibrils) and nonstriated (premyofibrils) actin fibers within 30 minutes, as determined by phalloidin stainings of the polymerized actin and troponin T stainings. Immunoblot analyses and immunostainings have indicated that cardiac myocytes express RhoA, but RhoB is undetectable. In the control state, RhoA was observed predominantly in the cytosolic fraction, but it was translocated in part to the particulate fraction in response to Ang II, consistent with activation of RhoA by Ang II. Incubation of myocytes with exoenzyme C3 for 48 hours completely ADP-ribosylated Rho in vivo. The C3 treatment abolished formation of premyofibrils induced by Ang II, suggesting that Ang II causes premyofibril formation via a Rho-dependent mechanism. The Ang II\u2013induced mature myofibril formation was only partly abolished by C3. Expression of constitutively active RhoA (V14RhoA) caused the formation of premyofibrils but not mature myofibrils. The C3 treatment inhibited Ang II\u2013induced atrial natriuretic factor induction, whereas it had no effect on c-\n            <jats:italic>fos</jats:italic>\n            induction. These results indicate that RhoA is activated by Ang II and mediates the Ang II\u2013induced formation of premyofibrils and induction of a subset of genes. Distinct signaling mechanisms seem to be responsible for striated mature myofibril formation by Ang II.\n          </jats:p>",
  "DOI": "10.1161/01.res.82.6.666",
  "type": "journal-article",
  "created": {
    "date-parts": [
      [
        2012,
        6,
        12
      ]
    ],
    "date-time": "2012-06-12T00:47:05Z",
    "timestamp": 1339462025000
  },
  "page": "666-676",
  "update-policy": "http://dx.doi.org/10.1161/crossmarkpolicy",
  "source": "Crossref",
  "is-referenced-by-count": 170,
  "title": "Angiotensin II Activates RhoA in Cardiac Myocytes",
  "prefix": "10.1161",
  "volume": "82",
  "author": [
    {
      "given": "Hiroki",
      "family": "Aoki",
      "sequence": "first",
      "affiliation": [
        {
          "name": "From the Cardiovascular Research Center, Division of Cardiology, University of Michigan Medical Center, Ann Arbor."
        }
      ]
    },
    {
      "given": "Seigo",
      "family": "Izumo",
      "sequence": "additional",
      "affiliation": [
        {
          "name": "From the Cardiovascular Research Center, Division of Cardiology, University of Michigan Medical Center, Ann Arbor."
        }
      ]
    },
    {
      "given": "Junichi",
      "family": "Sadoshima",
      "sequence": "additional",
      "affiliation": [
        {
          "name": "From the Cardiovascular Research Center, Division of Cardiology, University of Michigan Medical Center, Ann Arbor."
        }
      ]
    }
  ],
  "member": "276",
  "reference": [
    {
      "key": "e_1_3_2_1_2",
      "doi-asserted-by": "publisher",
      "DOI": "10.1126/science.2116664"
    },
    {
      "key": "e_1_3_2_2_2",
      "doi-asserted-by": "publisher",
      "DOI": "10.1016/S0955-0674(97)80156-1"
    },
    {
      "key": "e_1_3_2_3_2",
      "doi-asserted-by": "publisher",
      "DOI": "10.1016/0092-8674(92)90163-7"
    },
    {
      "key": "e_1_3_2_4_2",
      "doi-asserted-by": "publisher",
      "DOI": "10.1016/0092-8674(92)90164-8"
    },
    {
      "key": "e_1_3_2_5_2",
      "doi-asserted-by": "publisher",
      "DOI": "10.1016/0092-8674(95)90370-4"
    },
    {
      "key": "e_1_3_2_6_2",
      "doi-asserted-by": "publisher",
      "DOI": "10.1126/science.275.5304.1308"
    },
    {
      "key": "e_1_3_2_7_2",
      "doi-asserted-by": "publisher",
      "DOI": "10.1146/annurev.ph.55.030193.000453"
    },
    {
      "key": "e_1_3_2_8_2",
      "doi-asserted-by": "publisher",
      "DOI": "10.1146/annurev.ph.51.030189.001201"
    },
    {
      "key": "e_1_3_2_9_2",
      "doi-asserted-by": "publisher",
      "DOI": "10.1146/annurev.ph.55.030193.000415"
    },
    {
      "key": "e_1_3_2_10_2",
      "doi-asserted-by": "publisher",
      "DOI": "10.1146/annurev.ph.53.030191.001143"
    },
    {
      "key": "e_1_3_2_11_2",
      "doi-asserted-by": "publisher",
      "DOI": "10.1146/annurev.physiol.59.1.551"
    },
    {
      "key": "e_1_3_2_12_2",
      "first-page": "977",
      "volume": "75",
      "year": "1993",
      "unstructured": "Sadoshima J, Xu Y, Slayter HS, Izumo S. Autocrine release of angiotensin II mediates stretch-induced hypertrophy of cardiac myocytes in vitro. Cell. 1993;75:977\u2013984.",
      "journal-title": "in vitro. Cell"
    },
    {
      "key": "e_1_3_2_13_2",
      "doi-asserted-by": "publisher",
      "DOI": "10.1161/res.77.2.258"
    },
    {
      "key": "e_1_3_2_14_2",
      "doi-asserted-by": "publisher",
      "DOI": "10.1146/annurev.ph.54.030192.001303"
    },
    {
      "key": "e_1_3_2_15_2",
      "doi-asserted-by": "publisher",
      "DOI": "10.1161/res.73.3.8348686"
    },
    {
      "key": "e_1_3_2_16_2",
      "doi-asserted-by": "publisher",
      "DOI": "10.1161/res.73.3.8348687"
    },
    {
      "key": "e_1_3_2_17_2",
      "unstructured": "Aoki H Sadoshima J Izumo S. The role of mitogen-activated protein kinases in angiotensin II-induced cardiac hypertrophic responses in neonatal rat cardiac myocytes in vitro [abstract]. Circulation. 1996;94(suppl I):I-552."
    },
    {
      "key": "e_1_3_2_18_2",
      "doi-asserted-by": "publisher",
      "DOI": "10.1161/res.77.6.1040"
    },
    {
      "key": "e_1_3_2_19_2",
      "doi-asserted-by": "publisher",
      "DOI": "10.1083/jcb.99.6.2268"
    },
    {
      "key": "e_1_3_2_20_2",
      "doi-asserted-by": "publisher",
      "DOI": "10.1002/cm.970280102"
    },
    {
      "key": "e_1_3_2_21_2",
      "doi-asserted-by": "publisher",
      "DOI": "10.1083/jcb.117.5.1007"
    },
    {
      "key": "e_1_3_2_22_2",
      "doi-asserted-by": "publisher",
      "DOI": "10.1073/pnas.94.17.9493"
    },
    {
      "key": "e_1_3_2_23_2",
      "first-page": "273",
      "volume": "9",
      "year": "1994",
      "unstructured": "Takaishi K, Sasaki T, Kato M, Yamochi W, Kuroda S, Nakamura T, Takeichi M, Takai Y. Involvement of Rho p21 small GTP-binding protein and its regulator in the HGF-induced cell motility. Oncogene. 1994;9:273\u2013279.",
      "journal-title": "Oncogene"
    },
    {
      "key": "e_1_3_2_24_2",
      "doi-asserted-by": "publisher",
      "DOI": "10.1074/jbc.272.10.6136"
    },
    {
      "key": "e_1_3_2_25_2",
      "doi-asserted-by": "publisher",
      "DOI": "10.1016/0922-4106(95)90012-8"
    },
    {
      "key": "e_1_3_2_26_2",
      "doi-asserted-by": "publisher",
      "DOI": "10.1016/0014-5793(94)01148-6"
    },
    {
      "key": "e_1_3_2_27_2",
      "doi-asserted-by": "publisher",
      "DOI": "10.1016/S0021-9258(19)50052-7"
    },
    {
      "key": "e_1_3_2_28_2",
      "doi-asserted-by": "crossref",
      "unstructured": "Morii N Narumiya S. Preparation of native and recombinant Clostridium botulinum C3 ADP-ribosyltransferase and identification of Rho proteins by ADP-ribosylation. In: Balch WE Der CJ Hall A eds. Methods in Enzymology. San Diego Calif: Academic Press Inc; 1995;256:196\u2013206.",
      "DOI": "10.1016/0076-6879(95)56024-6"
    },
    {
      "key": "e_1_3_2_29_2",
      "doi-asserted-by": "publisher",
      "DOI": "10.1002/j.1460-2075.1995.tb00186.x"
    },
    {
      "key": "e_1_3_2_30_2",
      "doi-asserted-by": "publisher",
      "DOI": "10.1016/S0092-8674(05)80020-0"
    },
    {
      "key": "e_1_3_2_31_2",
      "doi-asserted-by": "publisher",
      "DOI": "10.1016/S0021-9258(18)31748-4"
    },
    {
      "key": "e_1_3_2_32_2",
      "doi-asserted-by": "publisher",
      "DOI": "10.1083/jcb.119.3.617"
    },
    {
      "key": "e_1_3_2_33_2",
      "doi-asserted-by": "publisher",
      "DOI": "10.1016/S0021-9258(19)50014-X"
    },
    {
      "key": "e_1_3_2_34_2",
      "doi-asserted-by": "publisher",
      "DOI": "10.1016/S0021-9258(18)81834-8"
    },
    {
      "key": "e_1_3_2_35_2",
      "doi-asserted-by": "publisher",
      "DOI": "10.1083/jcb.111.3.1001"
    },
    {
      "key": "e_1_3_2_36_2",
      "doi-asserted-by": "crossref",
      "unstructured": "Aktories K Just I. In vitro ADP-ribosylation of Rho by bacterial ADP-ribosyltransferases. In: Balch WE Der CJ Hall A eds. Methods in Enzymology. San Diego Calif: Academic Press Inc; 1995;256:184\u2013195.",
      "DOI": "10.1016/0076-6879(95)56023-8"
    },
    {
      "key": "e_1_3_2_37_2",
      "first-page": "237",
      "volume": "54",
      "year": "1991",
      "unstructured": "Wiegers W, Just I, Muller H, Hellwig A, Traub P, Aktories K. Alteration of the cytoskeleton of mammalian cells cultured in vitro by Clostridium botulinum C2 toxin and C3 ADP-ribosyltransferase. Eur J Cell Biol. 1991;54:237\u2013245.",
      "journal-title": "Eur J Cell Biol"
    },
    {
      "key": "e_1_3_2_38_2",
      "doi-asserted-by": "publisher",
      "DOI": "10.1074/jbc.271.49.31185"
    },
    {
      "key": "e_1_3_2_39_2",
      "doi-asserted-by": "publisher",
      "DOI": "10.1016/S0021-9258(19)74497-4"
    },
    {
      "key": "e_1_3_2_40_2",
      "doi-asserted-by": "publisher",
      "DOI": "10.1074/jbc.271.42.25731"
    },
    {
      "key": "e_1_3_2_41_2",
      "doi-asserted-by": "publisher",
      "DOI": "10.1002/j.1460-2075.1996.tb00383.x"
    },
    {
      "key": "e_1_3_2_42_2",
      "doi-asserted-by": "publisher",
      "DOI": "10.1074/jbc.272.16.10704"
    },
    {
      "key": "e_1_3_2_43_2",
      "doi-asserted-by": "publisher",
      "DOI": "10.1074/jbc.271.51.33067"
    },
    {
      "key": "e_1_3_2_44_2",
      "first-page": "39",
      "volume": "11",
      "year": "1995",
      "unstructured": "Takaishi K, Sasaki T, Kameyama T, Tsukita S, Tsukita S, Takai Y. Translocation of activated Rho from the cytoplasm to membrane ruffling area, cell-cell adhesion sites and cleavage furrows. Oncogene. 1995;11:39\u201348.",
      "journal-title": "Oncogene"
    },
    {
      "key": "e_1_3_2_45_2",
      "doi-asserted-by": "publisher",
      "DOI": "10.1242/jcs.108.1.225"
    },
    {
      "key": "e_1_3_2_46_2",
      "doi-asserted-by": "publisher",
      "DOI": "10.1161/01.RES.76.1.1"
    },
    {
      "key": "e_1_3_2_47_2",
      "doi-asserted-by": "publisher",
      "DOI": "10.1002/j.1460-2075.1996.tb00413.x"
    },
    {
      "key": "e_1_3_2_48_2",
      "doi-asserted-by": "publisher",
      "DOI": "10.1161/res.77.6.1053"
    },
    {
      "key": "e_1_3_2_49_2",
      "doi-asserted-by": "publisher",
      "DOI": "10.1161/res.80.5.607"
    },
    {
      "key": "e_1_3_2_50_2",
      "doi-asserted-by": "publisher",
      "DOI": "10.1074/jbc.270.16.9031"
    },
    {
      "key": "e_1_3_2_51_2",
      "doi-asserted-by": "publisher",
      "DOI": "10.1074/jbc.271.44.27374"
    },
    {
      "key": "e_1_3_2_52_2",
      "doi-asserted-by": "publisher",
      "DOI": "10.1002/(SICI)1097-4644(19970701)66:1<43::AID-JCB6>3.0.CO;2-Y"
    },
    {
      "key": "e_1_3_2_53_2",
      "doi-asserted-by": "publisher",
      "DOI": "10.1093/emboj/16.8.1888"
    },
    {
      "key": "e_1_3_2_54_2",
      "doi-asserted-by": "publisher",
      "DOI": "10.1091/mbc.8.4.705"
    },
    {
      "key": "e_1_3_2_55_2",
      "doi-asserted-by": "publisher",
      "DOI": "10.1073/pnas.85.2.482"
    },
    {
      "key": "e_1_3_2_56_2",
      "doi-asserted-by": "publisher",
      "DOI": "10.1016/S0960-9822(96)00749-X"
    },
    {
      "key": "e_1_3_2_57_2",
      "doi-asserted-by": "publisher",
      "DOI": "10.1161/01.RES.80.3.383"
    },
    {
      "key": "e_1_3_2_58_2",
      "doi-asserted-by": "publisher",
      "DOI": "10.1083/jcb.139.1.115"
    },
    {
      "key": "e_1_3_2_59_2",
      "doi-asserted-by": "publisher",
      "DOI": "10.1242/jcs.109.5.1133"
    },
    {
      "key": "e_1_3_2_60_2",
      "doi-asserted-by": "publisher",
      "DOI": "10.1016/S0955-0674(96)80059-7"
    },
    {
      "key": "e_1_3_2_61_2",
      "doi-asserted-by": "publisher",
      "DOI": "10.1042/bj3100741"
    },
    {
      "key": "e_1_3_2_62_2",
      "doi-asserted-by": "publisher",
      "DOI": "10.1161/res.81.5.672"
    }
  ],
  "container-title": "Circulation Research",
  "original-title": [],
  "language": "en",
  "link": [
    {
      "URL": "https://www.ahajournals.org/doi/full/10.1161/01.RES.82.6.666",
      "content-type": "unspecified",
      "content-version": "vor",
      "intended-application": "similarity-checking"
    }
  ],
  "deposited": {
    "date-parts": [
      [
        2024,
        5,
        12
      ]
    ],
    "date-time": "2024-05-12T20:46:43Z",
    "timestamp": 1715546803000
  },
  "score": 1,
  "resource": {
    "primary": {
      "URL": "https://www.ahajournals.org/doi/10.1161/01.RES.82.6.666"
    }
  },
  "subtitle": [
    "A Critical Role of RhoA in Angiotensin II\u2013Induced Premyofibril Formation"
  ],
  "short-title": [],
  "issued": {
    "date-parts": [
      [
        1998,
        4,
        6
      ]
    ]
  },
  "references-count": 62,
  "journal-issue": {
    "issue": "6",
    "published-print": {
      "date-parts": [
        [
          1998,
          4,
          6
        ]
      ]
    }
  },
  "alternative-id": [
    "10.1161/01.RES.82.6.666"
  ],
  "URL": "http://dx.doi.org/10.1161/01.RES.82.6.666",
  "relation": {},
  "ISSN": [
    "0009-7330",
    "1524-4571"
  ],
  "subject": [],
  "container-title-short": "Circulation Research",
  "published": {
    "date-parts": [
      [
        1998,
        4,
        6
      ]
    ]
  },
  "assertion": [
    {
      "value": "1997-11-25",
      "order": 0,
      "name": "received",
      "label": "Received",
      "group": {
        "name": "publication_history",
        "label": "Publication History"
      }
    },
    {
      "value": "1998-01-28",
      "order": 1,
      "name": "accepted",
      "label": "Accepted",
      "group": {
        "name": "publication_history",
        "label": "Publication History"
      }
    },
    {
      "value": "1998-04-06",
      "order": 2,
      "name": "published",
      "label": "Published",
      "group": {
        "name": "publication_history",
        "label": "Publication History"
      }
    }
  ]
}