title: Titin-Based Cardiac Myocyte Stiffening Contributes to Early Adaptive Ventricular Remodeling After Myocardial Infarction.
abstract: BACKGROUND
  Myocardial infarction (MI) increases the wall stress in the viable myocardium and initiates early adaptive remodeling in the left ventricle to maintain cardiac output. Later remodeling processes include fibrotic reorganization that eventually leads to cardiac failure. Understanding the mechanisms that support cardiac function in the early phase post MI and identifying the processes that initiate transition to maladaptive remodeling are of major clinical interest.
  
  
  OBJECTIVE
  To characterize MI-induced changes in titin-based cardiac myocyte stiffness and to elucidate the role of titin in ventricular remodeling of remote myocardium in the early phase after MI.
  
  
  RESULTS
  Titin properties were analyzed in Langendorff-perfused mouse hearts after 20-minute ischemia/60-minute reperfusion (I/R), and mouse hearts that underwent ligature of the left anterior descending coronary artery for 3 or 10 days. Cardiac myocyte passive tension was significantly increased 1 hour after ischemia/reperfusion and 3 and 10 days after left anterior descending coronary artery ligature. The increased passive tension was caused by hypophosphorylation of the titin N2-B unique sequence and hyperphosphorylation of the PEVK (titin domain rich in proline, glutamate, valine, and lysine) region of titin. Blocking of interleukine-6 before left anterior descending coronary artery ligature restored titin-based myocyte tension after MI, suggesting that MI-induced titin stiffening is mediated by elevated levels of the cytokine interleukine-6. We further demonstrate that the early remodeling processes 3 days after MI involve accelerated titin turnover by the ubiquitin-proteasome system.
  
  
  CONCLUSIONS
  We conclude that titin-based cardiac myocyte stiffening acutely after MI is partly mediated by interleukine-6 and is an important mechanism of remote myocardium to adapt to the increased mechanical demands after myocardial injury.
authors.affiliation: From the Department of Cardiovascular Physiology (S.K., M.K., C.A., K.B., A.H., A.G., M.K.), Department of Pharmacology and Clinical Pharmacology (M.G., S.G., J.W.F., J.P.S.), and Institute of Biochemistry and Molecular Biology II (J.M.M., J.S.), Medical Faculty, Heinrich-Heine University Düsseldorf, Germany.
authors.forename: Sebastian
authors.initials: S
authors.lastname: Kötter
authors.affiliation: From the Department of Cardiovascular Physiology (S.K., M.K., C.A., K.B., A.H., A.G., M.K.), Department of Pharmacology and Clinical Pharmacology (M.G., S.G., J.W.F., J.P.S.), and Institute of Biochemistry and Molecular Biology II (J.M.M., J.S.), Medical Faculty, Heinrich-Heine University Düsseldorf, Germany.
authors.forename: Malgorzata
authors.initials: M
authors.lastname: Kazmierowska
authors.affiliation: From the Department of Cardiovascular Physiology (S.K., M.K., C.A., K.B., A.H., A.G., M.K.), Department of Pharmacology and Clinical Pharmacology (M.G., S.G., J.W.F., J.P.S.), and Institute of Biochemistry and Molecular Biology II (J.M.M., J.S.), Medical Faculty, Heinrich-Heine University Düsseldorf, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Andresen
authors.affiliation: From the Department of Cardiovascular Physiology (S.K., M.K., C.A., K.B., A.H., A.G., M.K.), Department of Pharmacology and Clinical Pharmacology (M.G., S.G., J.W.F., J.P.S.), and Institute of Biochemistry and Molecular Biology II (J.M.M., J.S.), Medical Faculty, Heinrich-Heine University Düsseldorf, Germany.
authors.forename: Katharina
authors.initials: K
authors.lastname: Bottermann
authors.affiliation: From the Department of Cardiovascular Physiology (S.K., M.K., C.A., K.B., A.H., A.G., M.K.), Department of Pharmacology and Clinical Pharmacology (M.G., S.G., J.W.F., J.P.S.), and Institute of Biochemistry and Molecular Biology II (J.M.M., J.S.), Medical Faculty, Heinrich-Heine University Düsseldorf, Germany.
authors.forename: Maria
authors.initials: M
authors.lastname: Grandoch
authors.affiliation: From the Department of Cardiovascular Physiology (S.K., M.K., C.A., K.B., A.H., A.G., M.K.), Department of Pharmacology and Clinical Pharmacology (M.G., S.G., J.W.F., J.P.S.), and Institute of Biochemistry and Molecular Biology II (J.M.M., J.S.), Medical Faculty, Heinrich-Heine University Düsseldorf, Germany.
authors.forename: Simone
authors.initials: S
authors.lastname: Gorressen
authors.affiliation: From the Department of Cardiovascular Physiology (S.K., M.K., C.A., K.B., A.H., A.G., M.K.), Department of Pharmacology and Clinical Pharmacology (M.G., S.G., J.W.F., J.P.S.), and Institute of Biochemistry and Molecular Biology II (J.M.M., J.S.), Medical Faculty, Heinrich-Heine University Düsseldorf, Germany.
authors.forename: Andre
authors.initials: A
authors.lastname: Heinen
authors.affiliation: From the Department of Cardiovascular Physiology (S.K., M.K., C.A., K.B., A.H., A.G., M.K.), Department of Pharmacology and Clinical Pharmacology (M.G., S.G., J.W.F., J.P.S.), and Institute of Biochemistry and Molecular Biology II (J.M.M., J.S.), Medical Faculty, Heinrich-Heine University Düsseldorf, Germany.
authors.forename: Jens M
authors.initials: JM
authors.lastname: Moll
authors.affiliation: From the Department of Cardiovascular Physiology (S.K., M.K., C.A., K.B., A.H., A.G., M.K.), Department of Pharmacology and Clinical Pharmacology (M.G., S.G., J.W.F., J.P.S.), and Institute of Biochemistry and Molecular Biology II (J.M.M., J.S.), Medical Faculty, Heinrich-Heine University Düsseldorf, Germany.
authors.forename: Jürgen
authors.initials: J
authors.lastname: Scheller
authors.affiliation: From the Department of Cardiovascular Physiology (S.K., M.K., C.A., K.B., A.H., A.G., M.K.), Department of Pharmacology and Clinical Pharmacology (M.G., S.G., J.W.F., J.P.S.), and Institute of Biochemistry and Molecular Biology II (J.M.M., J.S.), Medical Faculty, Heinrich-Heine University Düsseldorf, Germany.
authors.forename: Axel
authors.initials: A
authors.lastname: Gödecke
authors.affiliation: From the Department of Cardiovascular Physiology (S.K., M.K., C.A., K.B., A.H., A.G., M.K.), Department of Pharmacology and Clinical Pharmacology (M.G., S.G., J.W.F., J.P.S.), and Institute of Biochemistry and Molecular Biology II (J.M.M., J.S.), Medical Faculty, Heinrich-Heine University Düsseldorf, Germany.
authors.forename: Jens W
authors.initials: JW
authors.lastname: Fischer
authors.affiliation: From the Department of Cardiovascular Physiology (S.K., M.K., C.A., K.B., A.H., A.G., M.K.), Department of Pharmacology and Clinical Pharmacology (M.G., S.G., J.W.F., J.P.S.), and Institute of Biochemistry and Molecular Biology II (J.M.M., J.S.), Medical Faculty, Heinrich-Heine University Düsseldorf, Germany.
authors.forename: Joachim P
authors.initials: JP
authors.lastname: Schmitt
authors.affiliation: From the Department of Cardiovascular Physiology (S.K., M.K., C.A., K.B., A.H., A.G., M.K.), Department of Pharmacology and Clinical Pharmacology (M.G., S.G., J.W.F., J.P.S.), and Institute of Biochemistry and Molecular Biology II (J.M.M., J.S.), Medical Faculty, Heinrich-Heine University Düsseldorf, Germany. martina.krueger@uni-duesseldorf.de.
authors.forename: Martina
authors.initials: M
authors.lastname: Krüger
mesh_terms: D000222:Adaptation, Physiological / Q000502:physiology*; D000818:Animals; D002478:Cells, Cultured; D064211:Connectin / Q000378:metabolism*; D005260:Female; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009203:Myocardial Infarction / Q000378:metabolism* / Q000473:pathology; D032383:Myocytes, Cardiac / Q000378:metabolism* / Q000473:pathology; D009924:Organ Culture Techniques; D010766:Phosphorylation / Q000502:physiology; D011247:Pregnancy; D051381:Rats; D017208:Rats, Wistar; D020257:Ventricular Remodeling / Q000502:physiology*
chemical_list: D064211:Connectin
keywords: cardiac output; chemokines; interleukin-6; myocardial infarction; myofibroblasts