Increased afterload induces pathological cardiac hypertrophy: a new in vitro model.
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Increased afterload induces pathological cardiac hypertrophy: a new in vitro model. / Hirt, Marc; Sörensen, Nils A.; Bartholdt, Lena M; Boeddinghaus, Jasper; Schaaf, Sebastian; Eder, Alexandra; Vollert, Ingra; Stöhr, Andrea; Schulze, Thomas; Witten, Anika; Stoll, Monika; Hansen, Arne; Eschenhagen, Thomas.
in: BASIC RES CARDIOL, Jahrgang 107, Nr. 6, 6, 2012, S. 307.Publikationen: SCORING: Beitrag in Fachzeitschrift/Zeitung › SCORING: Zeitschriftenaufsatz › Forschung › Begutachtung
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TY - JOUR
T1 - Increased afterload induces pathological cardiac hypertrophy: a new in vitro model.
AU - Hirt, Marc
AU - Sörensen, Nils A.
AU - Bartholdt, Lena M
AU - Boeddinghaus, Jasper
AU - Schaaf, Sebastian
AU - Eder, Alexandra
AU - Vollert, Ingra
AU - Stöhr, Andrea
AU - Schulze, Thomas
AU - Witten, Anika
AU - Stoll, Monika
AU - Hansen, Arne
AU - Eschenhagen, Thomas
PY - 2012
Y1 - 2012
N2 - Increased afterload results in 'pathological' cardiac hypertrophy, the most important risk factor for the development of heart failure. Current in vitro models fall short in deciphering the mechanisms of hypertrophy induced by afterload enhancement. The aim of this study was to develop an experimental model that allows investigating the impact of afterload enhancement (AE) on work-performing heart muscles in vitro. Fibrin-based engineered heart tissue (EHT) was cast between two hollow elastic silicone posts in a 24-well cell culture format. After 2 weeks, the posts were reinforced with metal braces, which markedly increased afterload of the spontaneously beating EHTs. Serum-free, triiodothyronine-, and hydrocortisone-supplemented medium conditions were established to prevent undefined serum effects. Control EHTs were handled identically without reinforcement. Endothelin-1 (ET-1)- or phenylephrine (PE)-stimulated EHTs served as positive control for hypertrophy. Cardiomyocytes in EHTs enlarged by 28.4 % under AE and to a similar extent by ET-1- or PE-stimulation (40.6 or 23.6 %), as determined by dystrophin staining. Cardiomyocyte hypertrophy was accompanied by activation of the fetal gene program, increased glucose consumption, and increased mRNA levels and extracellular deposition of collagen-1. Importantly, afterload-enhanced EHTs exhibited reduced contractile force and impaired diastolic relaxation directly after release of the metal braces. These deleterious effects of afterload enhancement were preventable by endothelin-A, but not endothelin-B receptor blockade. Sustained afterload enhancement of EHTs alone is sufficient to induce pathological cardiac remodeling with reduced contractile function and increased glucose consumption. The model will be useful to investigate novel therapeutic approaches in a simple and fast manner.
AB - Increased afterload results in 'pathological' cardiac hypertrophy, the most important risk factor for the development of heart failure. Current in vitro models fall short in deciphering the mechanisms of hypertrophy induced by afterload enhancement. The aim of this study was to develop an experimental model that allows investigating the impact of afterload enhancement (AE) on work-performing heart muscles in vitro. Fibrin-based engineered heart tissue (EHT) was cast between two hollow elastic silicone posts in a 24-well cell culture format. After 2 weeks, the posts were reinforced with metal braces, which markedly increased afterload of the spontaneously beating EHTs. Serum-free, triiodothyronine-, and hydrocortisone-supplemented medium conditions were established to prevent undefined serum effects. Control EHTs were handled identically without reinforcement. Endothelin-1 (ET-1)- or phenylephrine (PE)-stimulated EHTs served as positive control for hypertrophy. Cardiomyocytes in EHTs enlarged by 28.4 % under AE and to a similar extent by ET-1- or PE-stimulation (40.6 or 23.6 %), as determined by dystrophin staining. Cardiomyocyte hypertrophy was accompanied by activation of the fetal gene program, increased glucose consumption, and increased mRNA levels and extracellular deposition of collagen-1. Importantly, afterload-enhanced EHTs exhibited reduced contractile force and impaired diastolic relaxation directly after release of the metal braces. These deleterious effects of afterload enhancement were preventable by endothelin-A, but not endothelin-B receptor blockade. Sustained afterload enhancement of EHTs alone is sufficient to induce pathological cardiac remodeling with reduced contractile function and increased glucose consumption. The model will be useful to investigate novel therapeutic approaches in a simple and fast manner.
KW - Animals
KW - Cells, Cultured
KW - Rats
KW - Gene Expression
KW - Rats, Wistar
KW - Animals, Newborn
KW - Models, Biological
KW - Fibrosis
KW - Receptors, Endothelin/antagonists & inhibitors
KW - Tissue Engineering
KW - Rats, Inbred Lew
KW - Cardiomegaly/etiology
KW - Glycolysis
KW - Myocytes, Cardiac/physiology
KW - Animals
KW - Cells, Cultured
KW - Rats
KW - Gene Expression
KW - Rats, Wistar
KW - Animals, Newborn
KW - Models, Biological
KW - Fibrosis
KW - Receptors, Endothelin/antagonists & inhibitors
KW - Tissue Engineering
KW - Rats, Inbred Lew
KW - Cardiomegaly/etiology
KW - Glycolysis
KW - Myocytes, Cardiac/physiology
M3 - SCORING: Journal article
VL - 107
SP - 307
JO - BASIC RES CARDIOL
JF - BASIC RES CARDIOL
SN - 0300-8428
IS - 6
M1 - 6
ER -
