Abstract
Myocardial infarctions go along with biomechanical stress, i.e. stretching of muscle fibres, and the expression of certain marker molecules. We tested if two of those markers, endothelin-1 (ET-1) and growth differentiation factor 15 (GDF-15), can be used as immunohistochemical markers for myocardial ischaemia/infarctions. The study included experiments with an animal model, the isolated perfused Langendorff heart, as well as the investigation of human tissue samples drawn during autopsies. The overall picture of our results showed that GDF-15 is very sensitive and expressed very fast, not only as a consequence of ischaemia/infarctions, but also under other circumstances. Even an expression only caused by agony had to be discussed. ET-1, on the other hand, was less sensitive but only positive in those human cases with ischaemia/infarction that also showed typical alterations in conventional histology. Therefore, both markers did not proof to be a suitable diagnostic tool for myocardial infarctions. However, positive staining for ET-1 was also seen in rats’ hearts that suffered from arrhythmias after electric shock and in the myocardium of the right ventricle in human control cases in which a right heart failure has to be discussed. Thus, especially ET-1 should be subject of further studies that focus on these pathologies.
Similar content being viewed by others
References
Ortmann C, Pfeiffer H, Brinkmann B (2000) A comparative study on the immunohistochemical detection of early myocardial damage. Int J Legal Med 113:215–220
Sutton MGSJ, Sharpe N (2000) Left ventricular remodeling after myocardial infarction: pathophysiology and therapy. Circulation 101:2981–2988. https://doi.org/10.1161/01.CIR.101.25.2981
Cleutjens JP, Kandala JC, Guarda E et al (1995) Regulation of collagen degradation in the rat myocardium after infarction. J Mol Cell Cardiol 27:1281–1292
Tønnessen T, Giaid A, Saleh D et al (1995) Increased in vivo expression and production of endothelin-1 by porcine cardiomyocytes subjected to ischemia. Circ Res 76:767–772. https://doi.org/10.1161/01.RES.76.5.767
Kempf T (2006) The transforming growth factor-superfamily member growth-differentiation factor-15 protects the heart from ischemia/reperfusion injury. Circ Res 98:351–360. https://doi.org/10.1161/01.RES.0000202805.73038.48
Frank D, Kuhn C, Brors B et al (2008) Gene expression pattern in biomechanically stretched cardiomyocytes: evidence for a stretch-specific gene program. Hypertension 51:309–318. https://doi.org/10.1161/HYPERTENSIONAHA.107.098046
Cummings PM, Trelka DP, Springer KM (2011) Atlas of forensic histopathology. Cambridge University Press, Cambridge; New York
Thomsen H, Schulz A, Bhakdi S (1990) Immunhistochemische C5b-9-komplement-komplex-darstellung in frühstadien der herzmuskelnekrosen am paraffinschnitt. Int J Legal Med 103:199–206
Bi H, Yang Y, Huang J et al (2013) Immunohistochemical detection of S100A1 in the postmortem diagnosis of acute myocardial infarction. Diagn Pathol 8:84
Sabatasso S, Mangin P, Fracasso T et al (2016) Early markers for myocardial ischemia and sudden cardiac death. Int J Legal Med 130:1265–1280. https://doi.org/10.1007/s00414-016-1401-9
Mayer F, Falk M, Huhn R et al (2016) Dityrosine as a marker of acute myocardial infarction? Experiments with the isolated Langendorff heart. Int J Legal Med 130:1053–1060. https://doi.org/10.1007/s00414-016-1376-6
Bootcov MR, Bauskin AR, Valenzuela SM et al (1997) MIC-1, a novel macrophage inhibitory cytokine, is a divergent member of the TGF-beta superfamily. Proc Natl Acad Sci U S A 94:11514–11519
Shi Y, Massagué J (2003) Mechanisms of TGF-β signaling from cell membrane to the nucleus. Cell 113:685–700
Fairlie WD, Moore AG, Bauskin AR et al (1999) MIC-1 is a novel TGF-beta superfamily cytokine associated with macrophage activation. J Leukoc Biol 65:2–5
Hsiao EC, Koniaris LG, Zimmers-Koniaris T et al (2000) Characterization of growth-differentiation factor 15, a transforming growth factor β superfamily member induced following liver injury. Mol Cell Biol 20:3742–3751
Schernthaner C, Lichtenauer M, Wernly B et al (2017) Multibiomarker analysis in patients with acute myocardial infarction. Eur J Clin Investig 47:638–648. https://doi.org/10.1111/eci.12785
Kempf T, Zarbock A, Widera C et al (2011) GDF-15 is an inhibitor of leukocyte integrin activation required for survival after myocardial infarction in mice. Nat Med 17:581–588. https://doi.org/10.1038/nm.2354
Tzikas S, Palapies L, Bakogiannis C et al (2017) GDF-15 predicts cardiovascular events in acute chest pain patients. PLoS One 12:e0182314. https://doi.org/10.1371/journal.pone.0182314
Masaki T, Yanagisawa M, Goto K (1992) Physiology and pharmacology of endothelins. Med Res Rev 12:391–421
Yanagisawa M, Kurihara H, Kimura S et al (1988) A novel potent vasoconstrictor peptide produced by vascular endothelial cells. Nature 332:411–415. https://doi.org/10.1038/332411a0
Loennechen JP, Stoylen A, Beisvag V et al (2001) Regional expression of endothelin-1, ANP, IGF-1, and LV wall stress in the infarcted rat heart. Am J Phys 280:H2902–H2910
Oie E, Vinge LE, Tønnessen T et al (1997) Transient, isopeptide-specific induction of myocardial endothelin-1 mRNA in congestive heart failure in rats. Am J Phys 273:H1727–H1736
Tønnessen T, Lunde PK, Giaid A et al (1998) Pulmonary and cardiac expression of preproendothelin-1 mRNA are increased in heart failure after myocardial infarction in rats. Localization of preproendothelin-1 mRNA and endothelin peptide. Cardiovasc Res 39:633–643
Fishbein MC, Maclean D, Maroko PR (1978) Experimental myocardial infarction in the rat: qualitative and quantitative changes during pathologic evolution. Am J Pathol 90:57
Ono K, Matsumori A, Shioi T et al (1998) Cytokine gene expression after myocardial infarction in rat hearts: possible implication in left ventricular remodeling. Circulation 98:149–156
Yue P, Massie BM, Simpson PC, Long CS (1998) Cytokine expression increases in nonmyocytes from rats with postinfarction heart failure. Am J Physiol Heart Circ Physiol 275:H250–H258
Sakai S, Miyauchi T, Kobayashi M et al (1996) Inhibition of myocardial endothelin pathway improves long-term survival in heart failure. Nature 384:353–355. https://doi.org/10.1038/384353a0
Sütsch G, Kiowski W, Yan XW et al (1998) Short-term oral endothelin-receptor antagonist therapy in conventionally treated patients with symptomatic severe chronic heart failure. Circulation 98:2262–2268
Hirata Y, Takagi Y, Fukuda Y, Marumo F (1989) Endothelin is a potent mitogen for rat vascular smooth muscle cells. Atherosclerosis 78:225–228
Takuwa N, Takuwa Y, Yanagisawa M et al (1989) A novel vasoactive peptide endothelin stimulates mitogenesis through inositol lipid turnover in Swiss 3T3 fibroblasts. J Biol Chem 264:7856–7861
Ito H, Hirata Y, Hiroe M et al (1991) Endothelin-1 induces hypertrophy with enhanced expression of muscle-specific genes in cultured neonatal rat cardiomyocytes. Circ Res 69:209–215
Molenaar P, O’reilly G, Sharkey A et al (1993) Characterization and localization of endothelin receptor subtypes in the human atrioventricular conducting system and myocardium. Circ Res 72:526–538
Suzuki T, Kumazaki T, Mitsui Y (1993) Endothelin-1 is produced and secreted by neonatal rat cardiac myocytes in vitro. Biochem Biophys Res Commun 191:823–830. https://doi.org/10.1006/bbrc.1993.1291
Ito H, Hirata Y, Adachi S et al (1993) Endothelin-1 is an autocrine/paracrine factor in the mechanism of angiotensin II-induced hypertrophy in cultured rat cardiomyocytes. J Clin Invest 92:398–403. https://doi.org/10.1172/JCI116579
Fan Y, Li S, Li X-L et al (2016) Plasma endothelin-1 level as a predictor for poor collaterals in patients with ≥95% coronary chronic occlusion. Thromb Res 142:21–25. https://doi.org/10.1016/j.thromres.2016.04.007
Skovsted GF, Kruse LS, Berchtold LA et al (2017) Myocardial ischemia-reperfusion enhances transcriptional expression of endothelin-1 and vasoconstrictor ETB receptors via the protein kinase MEK-ERK1/2 signaling pathway in rat. PLoS One 12:e0174119. https://doi.org/10.1371/journal.pone.0174119
Shirai N, Naruko T, Ohsawa M et al (2006) Expression of endothelin-converting enzyme, endothelin-1 and endothelin receptors at the site of percutaneous coronary intervention in humans. J Hypertens 24:711–721. https://doi.org/10.1097/01.hjh.0000217854.97369.8c
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Falk, M., Huhn, R., Behmenburg, F. et al. Biomechanical stress in myocardial infarctions: can endothelin-1 and growth differentiation factor 15 serve as immunohistochemical markers?. Int J Legal Med 132, 509–518 (2018). https://doi.org/10.1007/s00414-017-1726-z
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00414-017-1726-z