Immediate mineralocorticoid receptor blockade improves myocardial infarct healing by modulation of the inflammatory response
Open accessAbstract
Mineralocorticoid receptor (MR) blockade reduces morbidity and mortality after acute myocardial infarction; however, the underlying mechanisms are still under investigation. This study examined whether MR antagonism promotes healing of the infarcted myocardium. Starting immediately after coronary ligation, male Wistar rats were treated with the selective MR antagonist eplerenone (100 mg/kg per day by gavage) or placebo for 2 to 7 days. At 7 days, eplerenone therapy versus placebo significantly reduced thinning and dilatation of the infarcted wall, improved left ventricular function, and enhanced neovessel formation in the injured myocardium. At 2 days, eplerenone-treated rats displayed lower plasma corticosterone levels, higher circulating blood monocytes, and more macrophages infiltrating the infarcted myocardium. MR blockade led to a transient upregulation (at days 2 and 3 but not at day 7) of monocyte chemoattractant protein-1, tumor necrosis factor-alpha, interleukin-1beta, interleukin-6, interleukin-10, and interleukin-4 and an increase in factor XIIIa protein expression in the healing myocardium. Prevention of macrophage accumulation into the infarct zone by treatment with liposome-encapsulated clodronate almost abrogated the protein expression of factor XIIIa and the beneficial effects of eplerenone on infarct expansion. In conclusion, selective MR blockade immediately after myocardial infarction accelerated macrophage infiltration and transiently increased the expression of healing promoting cytokines and factor XIIIa in the injured myocardium resulting in enhanced infarct neovascularization and reduced early LV dilation and dysfunction.
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
IL-4 gene expression is elevated from 1 to 7 days in rat skin wounds, and protein expression is elevated between 12 h and 10 days in human skin wounds.
“However, IL-4 gene expression is elevated from 1 to 7 days in rat skin wounds [56], and protein expression is elevated between 12 h and 10 days in human skin wounds (peak ϳ12 pg/mg protein in injured skin vs. nearly undetectable in uninjured) [58]; IL-4 protein is present at similar levels in infarcted rat myocardium [72].”
From Macrophage phenotypes during tissue repair (2013) · cites this paper as [72]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Cites
Alternative activation of macrophages
Gordon, S. (2003) · Nature Reviews Immunology · doi:10.1038/nri978 · Cited by 6,189 · see citing works
Pitt, B., Remme, W., Zannad, F., Neaton, J., Martinez, F., Roniker, B., Bittman, R., Hurley, S., Kleiman, J., & Gatlin, M. (2003) · New England Journal of Medicine · doi:10.1056/nejmoa030207 · Cited by 4,941 · see citing works
The inflammatory response in myocardial infarction
Frangogiannis, N. G. (2002) · Cardiovascular Research · doi:10.1016/s0008-6363(01)00434-5 · Cited by 2,013 · see citing works
van Rooijen, N., & Sanders, A. (1994) · Journal of Immunological Methods · doi:10.1016/0022-1759(94)90012-4 · Cited by 1,763 · see citing works
Opal, S. M., & DePalo, V. A. (2000) · Chest · doi:10.1378/chest.117.4.1162 · Cited by 1,752 · see citing works
The role of the macrophage in wound repair. A study with hydrocortisone and antimacrophage serum.
(1975) · PubMed Central · Cited by 1,437 · see citing works
Dewald, O., Zymek, P. T., Winkelmann, K., Koerting, A., Ren, G., Abou-Khamis, T., Michael, L. H., Rollins, B. J., Entman, M. L., & Frangogiannis, N. G. (2005) · Circulation Research · doi:10.1161/01.res.0000163017.13772.3a · Cited by 721 · see citing works
Aldosterone induces a vascular inflammatory phenotype in the rat heart
Rocha, R., Rudolph, A. E., Frierdich, G. E., Nachowiak, D. A., Kekec, B. K., Blomme, E. A. G., McMahon, E. G., & Delyani, J. A. (2002) · American Journal of Physiology-Heart and Circulatory Physiology · doi:10.1152/ajpheart.01096.2001 · Cited by 653 · see citing works
Aldosterone-Induced Inflammation in the Rat Heart
Sun, Y., Zhang, J., Lu, L., Chen, S. S., Quinn, M. T., & Weber, K. T. (2002) · American Journal Of Pathology · doi:10.1016/s0002-9440(10)64454-9 · Cited by 568 · see citing works
Pitt, B., White, H. D., Nicolau, J. C., Martínez, F. A., Gheorghiade, M., Aschermann, M., van Veldhuisen, D. J., Zannad, F. M., Krum, H., Mukherjee, R., et al. (2005) · Journal of the American College of Cardiology · doi:10.1016/j.jacc.2005.04.038 · Cited by 388 · see citing works
Healing after myocardial infarction.
Ertl, G., & Frantz, S. (2005) · Cardiovascular Research · doi:10.1016/j.cardiores.2005.01.011 · Cited by 331 · see citing works
Self-citationMechanisms of Mineralocorticoid Action
Fuller, P. J., & Young, M. J. (2005) · Hypertension · doi:10.1161/01.hyp.0000193502.77417.17 · Cited by 324 · see citing works
Hayashi, M., Tsutamoto, T., Wada, A., Tsutsui, T., Ishii, C., Ohno, K., Fujii, M., Taniguchi, A., Hamatani, T., Nozato, Y., et al. (2003) · Circulation · doi:10.1161/01.cir.0000068340.96506.0f · Cited by 319 · see citing works
Blood monocyte concentration is critical for enhancement of collateral artery growth
Heil, M., Ziegelhoeffer, T., Pipp, F. C., Sawa Kostin, D., Martin, S. M., Clauss, M. A., & Schaper, W. K. A. (2002) · American Journal of Physiology-Heart and Circulatory Physiology · doi:10.1152/ajpheart.01098.2001 · Cited by 303 · see citing works
Pierce, G. F., Mustoe, T. A., Lingelbach, J., Masakowski, V. R., Gramates, P. H., & Deuel, T. F. (1989) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.86.7.2229 · Cited by 301 · see citing works
Stress-Activated Cytokines and The Heart: From Adaptation to Maladaptation
Mann, D. L. (2003) · Annual Review of Physiology · doi:10.1146/annurev.physiol.65.092101.142249 · Cited by 299 · see citing works
Conditional Mineralocorticoid Receptor Expression in the Heart Leads to Life-Threatening Arrhythmias
Ouvrard‐Pascaud, A., Sainte–Marie, Y., Bénitah, J., Perrier, R., Soukaseum, C., Cat, A. N. D., Royer, A., Quang, K. L., Charpentier, F., Demolombe, S., et al. (2005) · Circulation · doi:10.1161/circulationaha.104.503706 · Cited by 271 · see citing works
Impaired Arteriogenic Response to Acute Hindlimb Ischemia in CD4-Knockout Mice
Stabile, E., Burnett, M. S., Watkins, C., et al. (2003) · Circulation · doi:10.1161/01.cir.0000079225.50817.71 · Cited by 268 · see citing works
Nagata, K., Obata, K., Xu, J., Ichihara, S., Noda, A., Kimata, H., Kato, T., Izawa, H., Murohara, T., & Yokota, M. (2006) · Hypertension · doi:10.1161/01.hyp.0000203772.78696.67 · Cited by 223 · see citing works
Birdsall, H. H., Green, D. M., Trial, J., Youker, K. A., Burns, A. R., Mackay, C. R., LaRosa, G. J., Hawkins, H. K., Smith, C. W., Michael, L. H., et al. (1997) · Circulation · doi:10.1161/01.cir.95.3.684 · Cited by 219 · see citing works
Suzuki, G., Morita, H., Mishima, T., Sharov, V. G., Todor, A. V., Tanhehco, E. J., Rudolph, A. E., McMahon, E. G., Goldstein, S., & Sabbah, H. N. (2002) · Circulation · doi:10.1161/01.cir.0000039104.56479.42 · Cited by 214 · see citing works
Fraccarollo, D., Galuppo, P., Hildemann, S. K., Christ, M., Ertl, G., & Bauersachs, J. K. (2003) · Journal of the American College of Cardiology · doi:10.1016/j.jacc.2003.05.003 · Cited by 169 · see citing works
Self-citationMorimoto, H., Takahashi, M., Izawa, A., Ise, H., Hongo, M., Kolattukudy, P. E., & Ikeda, U. (2006) · Circulation Research · doi:10.1161/01.res.0000246113.82111.2d · Cited by 165 · see citing works
Nahrendorf, M., Hu, K., Frantz, S., Jaffer, F. A., Tung, C., Hiller, K., Voll, S., Nordbeck, P., Sosnovik, D. E., Gattenlöhner, S., et al. (2006) · Circulation · doi:10.1161/circulationaha.105.602094 · Cited by 164 · see citing works
Self-citationEx Vivo Activated Human Macrophages Improve Healing, Remodeling, and Function of the Infarcted Heart
Leor, J., Rozen, L., Zuloff‐Shani, A., Feinberg, M. S., Amsalem, Y., Barbash, I. M., Kachel, E., Holbová, R., Mardor, Y., Daniels, D., et al. (2006) · Circulation · doi:10.1161/circulationaha.105.000331 · Cited by 156 · see citing works
Hwang, M., Matsumori, A., Furukawa, Y., Ono, K., Okada, M., Iwasaki, A., Hara, M., Miyamoto, T., Touma, M., & Sasayama, S. (2001) · Journal of the American College of Cardiology · doi:10.1016/s0735-1097(01)01591-1 · Cited by 149 · see citing works
Mummification of the infarcted myocardium by high dose corticosteroids.
Kloner, R. A., Fishbein, M. C., LEW, H., et al. (1978) · Circulation · doi:10.1161/01.cir.57.1.56 · Cited by 144 · see citing works
Perrier‐Groult, E., Kerfant, B., Lalevée, N., Bideaux, P., Rossier, M. F., Richard, S., Gomez, A. M., & Bénitah, J. (2004) · Circulation · doi:10.1161/01.cir.0000138973.55605.38 · Cited by 129 · see citing works
Small, G. R., Hadoke, P. W. F., Sharif, I., Dover, A. R., Armour, D. L., Kenyon, C. J., Gray, G. A., & Walker, B. R. (2005) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0500641102 · Cited by 119 · see citing works
The Role of Mineralocorticoid Receptors in Hypothalamic-Pituitary-Adrenal Axis Regulation in Humans1
Young, E. A., López, J. F., Murphy-Weinberg, V., Watson, S. J., & Akil, H. (1998) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jcem.83.9.5077 · Cited by 119 · see citing works
Identification of factor XIII-A as a marker of alternative macrophage activation
Törőcsik, D., Bárdos, H., Nagy, L., & Ádány, R. (2005) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-005-5242-9 · Cited by 115 · see citing works
Kobayashi, N., Yoshida, K., Nakano, S., Ohno, T., Honda, T., Tsubokou, Y., & Matsuoka, H. (2006) · Hypertension · doi:10.1161/01.hyp.0000203148.42892.7a · Cited by 110 · see citing works
Factor XIII (FXIII) and angiogenesis
Dardik, R., Loscalzo, J., & Inbal, A. (2005) · Journal of Thrombosis and Haemostasis · doi:10.1111/j.1538-7836.2005.01473.x · Cited by 97 · see citing works
Effect of a selective aldosterone receptor antagonist in myocardial infarction
Delyani, J. A., Robinson, E., & Rudolph, A. E. (2001) · American Journal of Physiology-Heart and Circulatory Physiology · doi:10.1152/ajpheart.2001.281.2.h647 · Cited by 97 · see citing works
Sartório, C. L., Fraccarollo, D., Galuppo, P., Leutke, M., Ertl, G., Stefanon, I., & Bauersachs, J. K. (2007) · Hypertension · doi:10.1161/hypertensionaha.107.093450 · Cited by 86 · see citing works
Self-citationYano, T., Miura, T., Whittaker, P., et al. (2006) · Journal of the American College of Cardiology · doi:10.1016/j.jacc.2005.09.037 · Cited by 74 · see citing works
Fraccarollo, D., Galuppo, P., Bauersachs, J. K., & Ertl, G. (2002) · Cardiovascular Research · doi:10.1016/s0008-6363(02)00256-0 · Cited by 68 · see citing works
Self-citationPROTECTING THE PUMP: Controlling Myocardial Inflammatory Responses
Taqueti, V. R., Mitchell, R. N., & Lichtman, A. H. (2005) · Annual Review of Physiology · doi:10.1146/annurev.physiol.68.040104.124611 · Cited by 64 · see citing works
Mannisi, J. A., Weisman, H. F., Bush, D. E., et al. (1987) · Journal of Clinical Investigation · doi:10.1172/jci112971 · Cited by 62 · see citing works
In vivo and in vitro inhibition of JE gene expression by glucocorticoids.
Poon, M., Megyesi, J., Green, R. S., Zhang, H., Rollins, B. J., Safirstein, R. L., & Taubman, M. B. (1991) · Journal of Biological Chemistry · doi:10.1016/s0021-9258(18)54582-8 · Cited by 56 · see citing works
Gemmati, D., Federici, F., Campo, G. C., Tognazzo, S., Serino, M. L., Mattei, M. D., Valgimigli, M., Malagutti, P., Guardigli, G., Ferraresi, P., et al. (2007) · Molecular Medicine · doi:10.2119/2006-00049.gemmati · Cited by 38 · see citing works
Monden, Y., Kubota, T., Tsutsumi, T., et al. (2006) · Cardiovascular Research · doi:10.1016/j.cardiores.2006.12.016 · Cited by 32 · see citing works
Pitt, B., & Pitt, G. S. (2007) · Circulation · doi:10.1161/circulationaha.106.670109 · Cited by 27 · see citing works
Inflammatory pathways and cardiac repair: the affliction of infarction
Knowlton, K. U., & Chien, K. R. (1999) · Nature Medicine · doi:10.1038/13441 · Cited by 23 · see citing works
Promise of Mineralocorticoid Receptor Blockade in Asymptomatic Left Ventricular Dysfunction
Pitt, B. (2007) · Hypertension · doi:10.1161/hypertensionaha.107.095356 · Cited by 2 · see citing works
Flagged first, then by citations
Research works printed but not linked: 1
- Fraccarollo D, Galuppo P, Bauersachs J, Ertl G. Collagen accumulation after myocardial infarction: effects of ETA receptor blockade and impli- cations for early remodeling. Cardiovasc Res. 2002;54:559 -567.
Cited by
Sorted by citations
Macrophage phenotypes during tissue repair
Novak, M. L., & Koh, T. J. (2013) · Journal of Leukocyte Biology · doi:10.1189/jlb.1012512 · Cited by 658 · see citing works
Finerenone and cardiovascular outcomes in patients with chronic kidney disease and type 2 diabetes
Filippatos, G., Anker, S. D., Agarwal, R., Pitt, B., Ruilope, L. M., Rossing, P., Kolkhof, P., Schloemer, P., Tornus, I., Joseph, A., et al. (2021) · Circulation · doi:10.1161/circulationaha.120.051898 · Cited by 294 · see citing works
- Authors
- Fraccarollo, D., Galuppo, P., Schraut, S., Kneitz, S., van Rooijen, N., Ertl, G., & Bauersachs, J.
- Affiliations
- University of Würzburg (DE)
- From the Medizinische Klinik und Poliklinik I (D.F., P.G., S.S., G.E., J.B.), Institut fuer Virologie and Immunbiologie (S.K.), Julius-Maximilians-Universität Würzburg, Würzburg, Germany; Department of Cell Biology (N.v.R.), Free University, Amsterdam, the Netherlands.
- Venue
- Hypertension
- Published
- 2008-04
- Volume
- 51
- Issue
- 4
- Pages
- 905-914
- ISSN
- 0194-911X (ISSN-L)
- 1524-4563
- OpenAlex
- W2160937709
- Cited by
- 133
- References
- 45
- Citations by year
- 2026: 4 · 2025: 3 · 2024: 3 · 2023: 3 · 2022: 6 · 2021: 5 · 2020: 7 · 2019: 6 · 2018: 10 · 2017: 4 · 2016: 4 · 2015: 7 · 2014: 15 · 2013: 14 · 2012: 8
- FWCI
- 8.24
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Hypertension (publishedVersion)
- PubMed (publishedVersion)
- Pure Amsterdam UMC (publishedVersion)
- Amsterdam UMC (VU Amsterdam) - Institutional Repository (publishedVersion)
- Data Archiving and Networked Services (DANS) (submittedVersion)
- Funders
- Pfizer
- Topics
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiac Fibrosis and Remodeling
- Health Sciences › Medicine › Pathology and Forensic Medicine › Cardiac Ischemia and Reperfusion
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Renin-Angiotensin System Studies
- Keywords
- mineralocorticoid receptor blockade, eplerenone, myocardial infarction, infarct healing, macrophage infiltration, MCP-1, cytokines, factor XIIIa, neovascularization, left ventricular dilatation, left ventricular function, clodronate liposomes, corticosterone, inflammation
- MeSH terms
- Eplerenone, Aldosterone, Mineralocorticoid Receptor Antagonists, Animals, Collagen, Clodronic Acid, Heart Failure, Humans, Male, Monocytes, Myocardial Infarction, Myocarditis, Myocardium, RNA, Messenger, Spironolactone, Wound Healing, Cytokines, Ventricular Function, Left, Rats, Wistar, Neovascularization, Physiologic, Factor XIIIa, Rats
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
