Skip to main content
Erschienen in: Inflammation 6/2019

22.07.2019 | Original Article

Characterization of Circular RNA and microRNA Profiles in Septic Myocardial Depression: a Lipopolysaccharide-Induced Rat Septic Shock Model

verfasst von: Tie-Ning Zhang, Ni Yang, Julie E. Goodwin, Kali Mahrer, Da Li, Jing Xia, Ri Wen, Han Zhou, Tao Zhang, Wen-Liang Song, Chun-Feng Liu

Erschienen in: Inflammation | Ausgabe 6/2019

Einloggen, um Zugang zu erhalten

Abstract

Septic shock with heart dysfunction is common in intensive care units. However, the mechanism underlying myocardial depression is still unclear. Whether circular RNA (circRNA) or microRNA (miRNA) profiles differ between patients with and without myocardial depression is unknown. We generated a hypodynamic septic shock model induced by lipopolysaccharide (LPS) in adolescent rats. A total of 12 rats were utilized and heart tissue from each was collected. RNA sequencing was performed on left ventricular tissue. We focused on features of circRNAs and miRNAs, predicting their function by bioinformatic analysis and constructing circRNA-associated and miRNA-associated regulatory networks in heart tissue. We detected 851 circRNAs in heart samples, and 11 showed differential expression. A total of 639 annotated miRNAs and 91 novel miRNAs were explored including 78 showing differential expression between the two groups. We then constructed the most comprehensive circRNA-associated and miRNA-associated networks to explore their regulatory relationship in septic heart tissue, and demonstrated that different networks could potentially participate in and regulate the pathological process of sepsis. Furthermore, gene ontology term enrichment indicated miRNAs, and miRNA-mRNA networks could be associated with regulation and metabolic process, or influence cellular functions. The construction of regulator networks could improve the understanding of the basic molecular mechanisms underlying myocardial depression. It will be important for future investigations to ascertain the biological mechanisms present during the development of sepsis-induced myocardial depression to influence approaches to treatment.
Anhänge
Nur mit Berechtigung zugänglich
Literatur
1.
Zurück zum Zitat Singer, M., C.S. Deutschman, C.W. Seymour, M. Shankar-Hari, D. Annane, M. Bauer, R. Bellomo, G.R. Bernard, J.D. Chiche, C.M. Coopersmith, R.S. Hotchkiss, M.M. Levy, J.C. Marshall, G.S. Martin, S.M. Opal, G.D. Rubenfeld, T. van der Poll, J.L. Vincent, and D.C. Angus. 2016. The third international consensus definitions for sepsis and septic shock (Sepsis-3). JAMA 315: 801–810.CrossRef Singer, M., C.S. Deutschman, C.W. Seymour, M. Shankar-Hari, D. Annane, M. Bauer, R. Bellomo, G.R. Bernard, J.D. Chiche, C.M. Coopersmith, R.S. Hotchkiss, M.M. Levy, J.C. Marshall, G.S. Martin, S.M. Opal, G.D. Rubenfeld, T. van der Poll, J.L. Vincent, and D.C. Angus. 2016. The third international consensus definitions for sepsis and septic shock (Sepsis-3). JAMA 315: 801–810.CrossRef
2.
Zurück zum Zitat Angus, D.C., and T. van der Poll. 2013. Severe sepsis and septic shock. The New England Journal of Medicine 369: 2063.CrossRef Angus, D.C., and T. van der Poll. 2013. Severe sepsis and septic shock. The New England Journal of Medicine 369: 2063.CrossRef
3.
Zurück zum Zitat Rhodes, A., L.E. Evans, W. Alhazzani, M.M. Levy, M. Antonelli, R. Ferrer, A. Kumar, J.E. Sevransky, C.L. Sprung, M.E. Nunnally, B. Rochwerg, G.D. Rubenfeld, D.C. Angus, D. Annane, R.J. Beale, G.J. Bellinghan, G.R. Bernard, J.D. Chiche, C. Coopersmith, D.P. De Backer, C.J. French, S. Fujishima, H. Gerlach, J.L. Hidalgo, S.M. Hollenberg, A.E. Jones, D.R. Karnad, R.M. Kleinpell, Y. Koh, T.C. Lisboa, F.R. Machado, J.J. Marini, J.C. Marshall, J.E. Mazuski, L.A. McIntyre, A.S. McLean, S. Mehta, R.P. Moreno, J. Myburgh, P. Navalesi, O. Nishida, T.M. Osborn, A. Perner, C.M. Plunkett, M. Ranieri, C.A. Schorr, M.A. Seckel, C.W. Seymour, L. Shieh, K.A. Shukri, S.Q. Simpson, M. Singer, B.T. Thompson, S.R. Townsend, T. Van der Poll, J.L. Vincent, W.J. Wiersinga, J.L. Zimmerman, and R.P. Dellinger. 2017. Surviving sepsis campaign: international guidelines for management of sepsis and septic shock: 2016. Intensive Care Medicine 43: 304–377.CrossRef Rhodes, A., L.E. Evans, W. Alhazzani, M.M. Levy, M. Antonelli, R. Ferrer, A. Kumar, J.E. Sevransky, C.L. Sprung, M.E. Nunnally, B. Rochwerg, G.D. Rubenfeld, D.C. Angus, D. Annane, R.J. Beale, G.J. Bellinghan, G.R. Bernard, J.D. Chiche, C. Coopersmith, D.P. De Backer, C.J. French, S. Fujishima, H. Gerlach, J.L. Hidalgo, S.M. Hollenberg, A.E. Jones, D.R. Karnad, R.M. Kleinpell, Y. Koh, T.C. Lisboa, F.R. Machado, J.J. Marini, J.C. Marshall, J.E. Mazuski, L.A. McIntyre, A.S. McLean, S. Mehta, R.P. Moreno, J. Myburgh, P. Navalesi, O. Nishida, T.M. Osborn, A. Perner, C.M. Plunkett, M. Ranieri, C.A. Schorr, M.A. Seckel, C.W. Seymour, L. Shieh, K.A. Shukri, S.Q. Simpson, M. Singer, B.T. Thompson, S.R. Townsend, T. Van der Poll, J.L. Vincent, W.J. Wiersinga, J.L. Zimmerman, and R.P. Dellinger. 2017. Surviving sepsis campaign: international guidelines for management of sepsis and septic shock: 2016. Intensive Care Medicine 43: 304–377.CrossRef
4.
Zurück zum Zitat Angus, D.C., W.T. Linde-Zwirble, J. Lidicker, G. Clermont, J. Carcillo, and M.R. Pinsky. 2001. Epidemiology of severe sepsis in the United States: analysis of incidence, outcome, and associated costs of care. Critical Care Medicine 29: 1303–1310.CrossRef Angus, D.C., W.T. Linde-Zwirble, J. Lidicker, G. Clermont, J. Carcillo, and M.R. Pinsky. 2001. Epidemiology of severe sepsis in the United States: analysis of incidence, outcome, and associated costs of care. Critical Care Medicine 29: 1303–1310.CrossRef
5.
Zurück zum Zitat Raj, S., J.S. Killinger, J.A. Gonzalez, and L. Lopez. 2014. Myocardial dysfunction in pediatric septic shock. The Journal of Pediatrics 164: 72–77.CrossRef Raj, S., J.S. Killinger, J.A. Gonzalez, and L. Lopez. 2014. Myocardial dysfunction in pediatric septic shock. The Journal of Pediatrics 164: 72–77.CrossRef
6.
Zurück zum Zitat Brierley, J., and M.J. Peters. 2008. Distinct hemodynamic patterns of septic shock at presentation to pediatric intensive care. Pediatrics 122: 752–759.CrossRef Brierley, J., and M.J. Peters. 2008. Distinct hemodynamic patterns of septic shock at presentation to pediatric intensive care. Pediatrics 122: 752–759.CrossRef
7.
Zurück zum Zitat Weiss, S.L., J.C. Fitzgerald, J. Pappachan, D. Wheeler, J.C. Jaramillo-Bustamante, A. Salloo, S.C. Singhi, S. Erickson, J.A. Roy, J.L. Bush, V.M. Nadkarni, and N.J. Thomas. 2015. Global epidemiology of pediatric severe sepsis: the sepsis prevalence, outcomes, and therapies study. American Journal of Respiratory and Critical Care Medicine 191: 1147–1157.CrossRef Weiss, S.L., J.C. Fitzgerald, J. Pappachan, D. Wheeler, J.C. Jaramillo-Bustamante, A. Salloo, S.C. Singhi, S. Erickson, J.A. Roy, J.L. Bush, V.M. Nadkarni, and N.J. Thomas. 2015. Global epidemiology of pediatric severe sepsis: the sepsis prevalence, outcomes, and therapies study. American Journal of Respiratory and Critical Care Medicine 191: 1147–1157.CrossRef
8.
Zurück zum Zitat Jeck, W.R., and N.E. Sharpless. 2014. Detecting and characterizing circular RNAs. Nature Biotechnology 32: 453–461.CrossRef Jeck, W.R., and N.E. Sharpless. 2014. Detecting and characterizing circular RNAs. Nature Biotechnology 32: 453–461.CrossRef
9.
Zurück zum Zitat Chen, L.L., and L. Yang. 2015. Regulation of circRNA biogenesis. RNA Biology 12: 381–388.CrossRef Chen, L.L., and L. Yang. 2015. Regulation of circRNA biogenesis. RNA Biology 12: 381–388.CrossRef
10.
Zurück zum Zitat Memczak, S., M. Jens, A. Elefsinioti, F. Torti, J. Krueger, A. Rybak, L. Maier, S.D. Mackowiak, L.H. Gregersen, M. Munschauer, A. Loewer, U. Ziebold, M. Landthaler, C. Kocks, F. le Noble, and N. Rajewsky. 2013. Circular RNAs are a large class of animal RNAs with regulatory potency. Nature 495: 333–338.CrossRef Memczak, S., M. Jens, A. Elefsinioti, F. Torti, J. Krueger, A. Rybak, L. Maier, S.D. Mackowiak, L.H. Gregersen, M. Munschauer, A. Loewer, U. Ziebold, M. Landthaler, C. Kocks, F. le Noble, and N. Rajewsky. 2013. Circular RNAs are a large class of animal RNAs with regulatory potency. Nature 495: 333–338.CrossRef
11.
Zurück zum Zitat Salzman, J., R.E. Chen, M.N. Olsen, P.L. Wang, and P.O. Brown. 2013. Cell-type specific features of circular RNA expression. PLoS Genetics 9: e1003777.CrossRef Salzman, J., R.E. Chen, M.N. Olsen, P.L. Wang, and P.O. Brown. 2013. Cell-type specific features of circular RNA expression. PLoS Genetics 9: e1003777.CrossRef
12.
Zurück zum Zitat Hansen, T.B., T.I. Jensen, B.H. Clausen, J.B. Bramsen, B. Finsen, C.K. Damgaard, and J. Kjems. 2013. Natural RNA circles function as efficient microRNA sponges. Nature 495: 384–388.CrossRef Hansen, T.B., T.I. Jensen, B.H. Clausen, J.B. Bramsen, B. Finsen, C.K. Damgaard, and J. Kjems. 2013. Natural RNA circles function as efficient microRNA sponges. Nature 495: 384–388.CrossRef
13.
Zurück zum Zitat Ho, J., H. Chan, S.H. Wong, M.H. Wang, J. Yu, Z. Xiao, X. Liu, G. Choi, C.C. Leung, W.T. Wong, Z. Li, T. Gin, M.T. Chan, and W.K. Wu. 2016. The involvement of regulatory non-coding RNAs in sepsis: a systematic review. Critical Care 20: 383.CrossRef Ho, J., H. Chan, S.H. Wong, M.H. Wang, J. Yu, Z. Xiao, X. Liu, G. Choi, C.C. Leung, W.T. Wong, Z. Li, T. Gin, M.T. Chan, and W.K. Wu. 2016. The involvement of regulatory non-coding RNAs in sepsis: a systematic review. Critical Care 20: 383.CrossRef
14.
Zurück zum Zitat Yang, N., X.L. Shi, B.L. Zhang, J. Rong, T.N. Zhang, W. Xu, and C.F. Liu. 2018. The trend of beta3-adrenergic receptor in the development of septic myocardial depression: a lipopolysaccharide-induced rat septic shock model. Cardiology 139: 234–244.CrossRef Yang, N., X.L. Shi, B.L. Zhang, J. Rong, T.N. Zhang, W. Xu, and C.F. Liu. 2018. The trend of beta3-adrenergic receptor in the development of septic myocardial depression: a lipopolysaccharide-induced rat septic shock model. Cardiology 139: 234–244.CrossRef
15.
Zurück zum Zitat Trapnell, C., B.A. Williams, G. Pertea, A. Mortazavi, G. Kwan, M.J. van Baren, S.L. Salzberg, B.J. Wold, and L. Pachter. 2010. Transcript assembly and quantification by RNA-Seq reveals unannotated transcripts and isoform switching during cell differentiation. Nature Biotechnology 28: 511–515.CrossRef Trapnell, C., B.A. Williams, G. Pertea, A. Mortazavi, G. Kwan, M.J. van Baren, S.L. Salzberg, B.J. Wold, and L. Pachter. 2010. Transcript assembly and quantification by RNA-Seq reveals unannotated transcripts and isoform switching during cell differentiation. Nature Biotechnology 28: 511–515.CrossRef
16.
Zurück zum Zitat Zhou, L., J. Chen, Z. Li, X. Li, X. Hu, Y. Huang, X. Zhao, C. Liang, Y. Wang, L. Sun, M. Shi, X. Xu, F. Shen, M. Chen, Z. Han, Z. Peng, Q. Zhai, J. Chen, Z. Zhang, R. Yang, J. Ye, Z. Guan, H. Yang, Y. Gui, J. Wang, Z. Cai, and X. Zhang. 2010. Integrated profiling of microRNAs and mRNAs: microRNAs located on Xq27.3 associate with clear cell renal cell carcinoma. Plos One 5: e15224.CrossRef Zhou, L., J. Chen, Z. Li, X. Li, X. Hu, Y. Huang, X. Zhao, C. Liang, Y. Wang, L. Sun, M. Shi, X. Xu, F. Shen, M. Chen, Z. Han, Z. Peng, Q. Zhai, J. Chen, Z. Zhang, R. Yang, J. Ye, Z. Guan, H. Yang, Y. Gui, J. Wang, Z. Cai, and X. Zhang. 2010. Integrated profiling of microRNAs and mRNAs: microRNAs located on Xq27.3 associate with clear cell renal cell carcinoma. Plos One 5: e15224.CrossRef
17.
Zurück zum Zitat Young, M.D., M.J. Wakefield, G.K. Smyth, and A. Oshlack. 2010. Gene ontology analysis for RNA-seq: accounting for selection bias. Genome Biology 11: R14.CrossRef Young, M.D., M.J. Wakefield, G.K. Smyth, and A. Oshlack. 2010. Gene ontology analysis for RNA-seq: accounting for selection bias. Genome Biology 11: R14.CrossRef
18.
Zurück zum Zitat Kanehisa, M., M. Araki, S. Goto, M. Hattori, M. Hirakawa, M. Itoh, T. Katayama, S. Kawashima, S. Okuda, T. Tokimatsu, and Y. Yamanishi. 2008. KEGG for linking genomes to life and the environment. Nucleic Acids Re 36 (Database issue): D480–D484. Kanehisa, M., M. Araki, S. Goto, M. Hattori, M. Hirakawa, M. Itoh, T. Katayama, S. Kawashima, S. Okuda, T. Tokimatsu, and Y. Yamanishi. 2008. KEGG for linking genomes to life and the environment. Nucleic Acids Re 36 (Database issue): D480–D484.
19.
Zurück zum Zitat Langmead, B., C. Trapnell, M. Pop, and S.L. Salzberg. 2009. Ultrafast and memory-efficient alignment of short DNA sequences to the human genome. Genome Biology 10: R25.CrossRef Langmead, B., C. Trapnell, M. Pop, and S.L. Salzberg. 2009. Ultrafast and memory-efficient alignment of short DNA sequences to the human genome. Genome Biology 10: R25.CrossRef
20.
Zurück zum Zitat Wen, M., Y. Shen, S. Shi, and T. Tang. 2012. miREvo: an integrative microRNA evolutionary analysis platform for next-generation sequencing experiments. BMC Bioinformatics 13: 140.CrossRef Wen, M., Y. Shen, S. Shi, and T. Tang. 2012. miREvo: an integrative microRNA evolutionary analysis platform for next-generation sequencing experiments. BMC Bioinformatics 13: 140.CrossRef
21.
Zurück zum Zitat Friedlander, M.R., S.D. Mackowiak, N. Li, W. Chen, and N. Rajewsky. 2012. miRDeep2 accurately identifies known and hundreds of novel microRNA genes in seven animal clades. Nucleic Acids Research 40: 37–52.CrossRef Friedlander, M.R., S.D. Mackowiak, N. Li, W. Chen, and N. Rajewsky. 2012. miRDeep2 accurately identifies known and hundreds of novel microRNA genes in seven animal clades. Nucleic Acids Research 40: 37–52.CrossRef
22.
Zurück zum Zitat Girardot, T., T. Rimmele, F. Venet, and G. Monneret. 2017. Apoptosis-induced lymphopenia in sepsis and other severe injuries. Apoptosis 22: 295–305.CrossRef Girardot, T., T. Rimmele, F. Venet, and G. Monneret. 2017. Apoptosis-induced lymphopenia in sepsis and other severe injuries. Apoptosis 22: 295–305.CrossRef
23.
Zurück zum Zitat Qi, J., Y. Qiao, P. Wang, S. Li, W. Zhao, and C. Gao. 2012. microRNA-210 negatively regulates LPS-induced production of proinflammatory cytokines by targeting NF-kappaB1 in murine macrophages. FEBS Letters 586: 1201–1207.CrossRef Qi, J., Y. Qiao, P. Wang, S. Li, W. Zhao, and C. Gao. 2012. microRNA-210 negatively regulates LPS-induced production of proinflammatory cytokines by targeting NF-kappaB1 in murine macrophages. FEBS Letters 586: 1201–1207.CrossRef
24.
Zurück zum Zitat Ma, H., X. Wang, T. Ha, M. Gao, L. Liu, R. Wang, K. Yu, J.H. Kalbfleisch, R.L. Kao, D.L. Williams, and C. Li. 2016. MicroRNA-125b prevents cardiac dysfunction in polymicrobial sepsis by targeting TRAF6-mediated nuclear factor kappaB activation and p53-mediated apoptotic signaling. The Journal of Infectious Diseases 214: 1773–1783.CrossRef Ma, H., X. Wang, T. Ha, M. Gao, L. Liu, R. Wang, K. Yu, J.H. Kalbfleisch, R.L. Kao, D.L. Williams, and C. Li. 2016. MicroRNA-125b prevents cardiac dysfunction in polymicrobial sepsis by targeting TRAF6-mediated nuclear factor kappaB activation and p53-mediated apoptotic signaling. The Journal of Infectious Diseases 214: 1773–1783.CrossRef
25.
Zurück zum Zitat Levy, M.M., A. Artigas, G.S. Phillips, A. Rhodes, R. Beale, T. Osborn, J.L. Vincent, S. Townsend, S. Lemeshow, and R.P. Dellinger. 2012. Outcomes of the surviving sepsis campaign in intensive care units in the USA and Europe: a prospective cohort study. The Lancet Infectious Diseases 12: 919–924.CrossRef Levy, M.M., A. Artigas, G.S. Phillips, A. Rhodes, R. Beale, T. Osborn, J.L. Vincent, S. Townsend, S. Lemeshow, and R.P. Dellinger. 2012. Outcomes of the surviving sepsis campaign in intensive care units in the USA and Europe: a prospective cohort study. The Lancet Infectious Diseases 12: 919–924.CrossRef
26.
Zurück zum Zitat Romero-Bermejo, F.J., M. Ruiz-Bailen, J. Gil-Cebrian, and M.J. Huertos-Ranchal. 2011. Sepsis-induced cardiomyopathy. Current Cardiology Reviews 7: 163–183.CrossRef Romero-Bermejo, F.J., M. Ruiz-Bailen, J. Gil-Cebrian, and M.J. Huertos-Ranchal. 2011. Sepsis-induced cardiomyopathy. Current Cardiology Reviews 7: 163–183.CrossRef
27.
Zurück zum Zitat Hochstadt, A., Y. Meroz, and G. Landesberg. 2011. Myocardial dysfunction in severe sepsis and septic shock: more questions than answers? Journal of Cardiothoracic and Vascular Anesthesia 25: 526–535.CrossRef Hochstadt, A., Y. Meroz, and G. Landesberg. 2011. Myocardial dysfunction in severe sepsis and septic shock: more questions than answers? Journal of Cardiothoracic and Vascular Anesthesia 25: 526–535.CrossRef
28.
Zurück zum Zitat Sluijter, J.P., and P.A. Doevendans. 2016. Sepsis-associated cardiac dysfunction is controlled by small RNA molecules. Journal of Molecular and Cellular Cardiology 97: 67–69.CrossRef Sluijter, J.P., and P.A. Doevendans. 2016. Sepsis-associated cardiac dysfunction is controlled by small RNA molecules. Journal of Molecular and Cellular Cardiology 97: 67–69.CrossRef
29.
Zurück zum Zitat Wang, X., W. Huang, Y. Yang, Y. Wang, T. Peng, J. Chang, C.C. Caldwell, B. Zingarelli, and G.C. Fan. 2014. Loss of duplexmiR-223 (5p and 3p) aggravates myocardial depression and mortality in polymicrobial sepsis. Biochimica et Biophysica Acta 1842: 701–711.CrossRef Wang, X., W. Huang, Y. Yang, Y. Wang, T. Peng, J. Chang, C.C. Caldwell, B. Zingarelli, and G.C. Fan. 2014. Loss of duplexmiR-223 (5p and 3p) aggravates myocardial depression and mortality in polymicrobial sepsis. Biochimica et Biophysica Acta 1842: 701–711.CrossRef
30.
Zurück zum Zitat Gao, M., X. Wang, X. Zhang, T. Ha, H. Ma, L. Liu, J.H. Kalbfleisch, X. Gao, R.L. Kao, D.L. Williams, and C. Li. 2015. Attenuation of cardiac dysfunction in polymicrobial sepsis by MicroRNA-146a is mediated via targeting of IRAK1 and TRAF6 expression. Journal of Immunology 195: 672–682.CrossRef Gao, M., X. Wang, X. Zhang, T. Ha, H. Ma, L. Liu, J.H. Kalbfleisch, X. Gao, R.L. Kao, D.L. Williams, and C. Li. 2015. Attenuation of cardiac dysfunction in polymicrobial sepsis by MicroRNA-146a is mediated via targeting of IRAK1 and TRAF6 expression. Journal of Immunology 195: 672–682.CrossRef
31.
Zurück zum Zitat Wang, H., Y. Bei, S. Shen, P. Huang, J. Shi, J. Zhang, Q. Sun, Y. Chen, Y. Yang, T. Xu, X. Kong, and J. Xiao. 2016. miR-21-3p controls sepsis-associated cardiac dysfunction via regulating SORBS2. Journal of Molecular and Cellular Cardiology 94: 43–53.CrossRef Wang, H., Y. Bei, S. Shen, P. Huang, J. Shi, J. Zhang, Q. Sun, Y. Chen, Y. Yang, T. Xu, X. Kong, and J. Xiao. 2016. miR-21-3p controls sepsis-associated cardiac dysfunction via regulating SORBS2. Journal of Molecular and Cellular Cardiology 94: 43–53.CrossRef
32.
Zurück zum Zitat Zhang, S., D. Zhu, H. Li, H. Li, C. Feng, and W. Zhang. 2017. Characterization of circRNA-associated-ceRNA networks in a senescence-accelerated mouse prone 8 brain. Molecular Therapy 25: 2053–2061.CrossRef Zhang, S., D. Zhu, H. Li, H. Li, C. Feng, and W. Zhang. 2017. Characterization of circRNA-associated-ceRNA networks in a senescence-accelerated mouse prone 8 brain. Molecular Therapy 25: 2053–2061.CrossRef
Metadaten
Titel
Characterization of Circular RNA and microRNA Profiles in Septic Myocardial Depression: a Lipopolysaccharide-Induced Rat Septic Shock Model
verfasst von
Tie-Ning Zhang
Ni Yang
Julie E. Goodwin
Kali Mahrer
Da Li
Jing Xia
Ri Wen
Han Zhou
Tao Zhang
Wen-Liang Song
Chun-Feng Liu
Publikationsdatum
22.07.2019
Verlag
Springer US
Erschienen in
Inflammation / Ausgabe 6/2019
Print ISSN: 0360-3997
Elektronische ISSN: 1573-2576
DOI
https://doi.org/10.1007/s10753-019-01060-8

Weitere Artikel der Ausgabe 6/2019

Inflammation 6/2019 Zur Ausgabe

Leitlinien kompakt für die Innere Medizin

Mit medbee Pocketcards sicher entscheiden.

Seit 2022 gehört die medbee GmbH zum Springer Medizin Verlag

Update Innere Medizin

Bestellen Sie unseren Fach-Newsletter und bleiben Sie gut informiert.