Bruno K Podesser1,2, Maximilian Kreibich1,3, Elda Dzilic1,4, David Santer1,5, Lorenz Förster6, Sandra Trojanek6, Dietmar Abraham6, Martin Krššák7, Klaus U Klein8, Eva V Tretter8, Christoph Kaun1, Johann Wojta1, Barbara Kapeller1, Inês Fonseca Gonçalves1, Karola Trescher1,2, Attila Kiss1. 1. Ludwig Boltzmann Cluster for Cardiovascular Research at the Center for Biomedical Research, Medical University of Vienna, Vienna. 2. Department of Cardiac Surgery, LK St. Poelten, St. Poelten, Austria. 3. Department of Cardiovascular Surgery, Heart Centre Freiburg University, Faculty of Medicine, University of Freiburg, Freiburg. 4. Department of Cardiovascular Surgery, German Heart Center Munich, Technische Universität München, Munich, Germany. 5. Department of Cardiovascular Surgery, Hospital Hietzing. 6. Laboratory for Molecular Cellular Biology, Medical University of Vienna. 7. Division of Endocrinology and Metabolism, Department of Internal Medicine III, Medical University of Vienna. 8. Department of Anesthesiology Intensive Care and Pain Therapy, Medical University of Vienna, Austria.
Abstract
AIMS: Left ventricular (LV) hypertrophy is characterized by cardiomyocyte hypertrophy and interstitial fibrosis ultimately leading to increased myocardial stiffness and reduced contractility. There is substantial evidence that the altered expression of matrix metalloproteinases (MMP) and Tenascin-C (TN-C) are associated with the progression of adverse LV remodeling. However, the role of TN-C in the development of LV hypertrophy because of chronic pressure overload as well as the regulatory role of TN-C on MMPs remains unknown. METHODS AND RESULTS: In a knockout mouse model of TN-C, we investigated the effect of 10 weeks of pressure overload using transverse aortic constriction (TAC). Cardiac function was determined by magnetic resonance imaging. The expression of MMP-2 and MMP-9, CD147 as well as myocardial fibrosis were assessed by immunohistochemistry. The expression of TN-C was assessed by RT-qPCR and ELISA. TN-C knockout mice showed marked reduction in fibrosis (P < 0.001) and individual cardiomyocytes size (P < 0.01), in expression of MMP-2 (P < 0.05) and MMP-9 (P < 0.001) as well as preserved cardiac function (P < 0.01) in comparison with wild-type mice after 10 weeks of TAC. In addition, CD147 expression was markedly increased under pressure overload (P < 0.01), irrespectively of genotype. TN-C significantly increased the expression of the markers of hypertrophy such as ANP and BNP as well as MMP-2 in H9c2 cells (P < 0.05, respectively). CONCLUSION: Our results are pointed toward a novel signaling mechanism that contributes to LV remodeling via MMPs upregulation, cardiomyocyte hypertrophy as well as myocardial fibrosis by TN-C under chronic pressure overload.
AIMS: Left ventricular (LV) hypertrophy is characterized by cardiomyocyte hypertrophy and interstitial fibrosis ultimately leading to increased myocardial stiffness and reduced contractility. There is substantial evidence that the altered expression of matrix metalloproteinases (MMP) and Tenascin-C (TN-C) are associated with the progression of adverse LV remodeling. However, the role of TN-C in the development of LV hypertrophy because of chronic pressure overload as well as the regulatory role of TN-C on MMPs remains unknown. METHODS AND RESULTS: In a knockout mouse model of TN-C, we investigated the effect of 10 weeks of pressure overload using transverse aortic constriction (TAC). Cardiac function was determined by magnetic resonance imaging. The expression of MMP-2 and MMP-9, CD147 as well as myocardial fibrosis were assessed by immunohistochemistry. The expression of TN-C was assessed by RT-qPCR and ELISA. TN-C knockout mice showed marked reduction in fibrosis (P < 0.001) and individual cardiomyocytes size (P < 0.01), in expression of MMP-2 (P < 0.05) and MMP-9 (P < 0.001) as well as preserved cardiac function (P < 0.01) in comparison with wild-type mice after 10 weeks of TAC. In addition, CD147 expression was markedly increased under pressure overload (P < 0.01), irrespectively of genotype. TN-C significantly increased the expression of the markers of hypertrophy such as ANP and BNP as well as MMP-2 in H9c2 cells (P < 0.05, respectively). CONCLUSION: Our results are pointed toward a novel signaling mechanism that contributes to LV remodeling via MMPs upregulation, cardiomyocyte hypertrophy as well as myocardial fibrosis by TN-C under chronic pressure overload.
Authors: Felix Nagel; Anne-Kristin Schaefer; Inês Fonseca Gonçalves; Eylem Acar; Andre Oszwald; Philipp Kaiser; Renate Kain; Karola Trescher; Wolf H Eilenberg; Christine Brostjan; David Santer; Attila Kiss; Bruno K Podesser Journal: Interact Cardiovasc Thorac Surg Date: 2022-05-02
Authors: David Santer; Felix Nagel; Inês Fonseca Gonçalves; Christoph Kaun; Johann Wojta; Miklós Fagyas; Martin Krššák; Ágnes Balogh; Zoltán Papp; Attila Tóth; Viktor Bánhegyi; Karola Trescher; Attila Kiss; Bruno K Podesser Journal: ESC Heart Fail Date: 2020-07-08
Authors: Kaj E C Blokland; Simon D Pouwels; Michael Schuliga; Darryl A Knight; Janette K Burgess Journal: Clin Sci (Lond) Date: 2020-10-30 Impact factor: 6.124
Authors: Petra Lujza Szabó; Janine Ebner; Xaver Koenig; Ouafa Hamza; Simon Watzinger; Sandra Trojanek; Dietmar Abraham; Hannes Todt; Helmut Kubista; Klaus Schicker; Séverine Remy; Ignacio Anegon; Attila Kiss; Bruno K Podesser; Karlheinz Hilber Journal: Dis Model Mech Date: 2021-02-22 Impact factor: 5.732