Kathrina Wiesen1, Elisabeth Kaiser2, Laura Schröder2, Anke Scholz2, Sandra Ruppenthal2, Jan-Christian Reil3, Christina Backes4, Eckart Meese4, Carola Meier5, Anna Bogdanova6, Peter Lipp7, Lars Kaestner8. 1. Institute of Veterinary Physiology, Vetsuisse Faculty and the Zürich Center for Integrative Human Physiology, University of Zürich, 8057 Zürich, Switzerland; Institute for Molecular Cell Biology and Research Centre for Molecular Imaging and Screening, Saarland University, 66421 Homburg/Saar, Germany. 2. Institute for Molecular Cell Biology and Research Centre for Molecular Imaging and Screening, Saarland University, 66421 Homburg/Saar, Germany. 3. Clinic for Internal Medicine III, Saarland University, 66421 Homburg/Saar, Germany. 4. Institute for Human Genetics, Saarland University, 66421 Homburg/Saar, Germany. 5. Anatomy, Saarland University, 66421 Homburg/Saar, Germany. 6. Institute of Veterinary Physiology, Vetsuisse Faculty and the Zürich Center for Integrative Human Physiology, University of Zürich, 8057 Zürich, Switzerland. 7. Institute for Molecular Cell Biology and Research Centre for Molecular Imaging and Screening, Saarland University, 66421 Homburg/Saar, Germany. Electronic address: peter.lipp@uks.eu. 8. Institute for Molecular Cell Biology and Research Centre for Molecular Imaging and Screening, Saarland University, 66421 Homburg/Saar, Germany. Electronic address: lars_kaestner@me.com.
Abstract
BACKGROUND: Although both Gαq- and Gα11-protein signaling are believed to be involved in the regulation of cardiac hypertrophy, their detailed contribution to myocardial function remains elusive. METHODS AND RESULTS: We studied remodeling processes in healthy transgenic mice with genetically altered Gαq/Gα11-expression, in particular a global Gα11-knockout and a novel inducible cardiac specific Gαq-knockout, as well as a combined double knockout (dKO) mouse line. Echocardiography and telemetric ECG recordings revealed that compared with wild type mice, hearts of dKO mice showed an increased ejection fraction and a decreased heart rate, irrespective of age resulting in a maintained cardiac output. We attributed these findings to the lack of Gα11, which the absence was associated with a decreased afterload. Histological analysis of the extracellular matrix in the heart depicted a diminished presence of collagen in aging hearts of dKO mice compared to wild-type mice. The results of a transcriptome analysis on isolated ventricular cardiac myocytes revealed alterations of the activity of genes involved in the Gαq/Gα11-dependent regulation of the extracellular matrix, such as the matricellular protein Cyr61. CONCLUSIONS: From our data we conclude that Gαq/Gα11 signaling pathways play a pivotal role in maintaining gene activity patterns. For the heart we revealed their importance in modulating the properties of the extracellular matrix, a mechanism that might be an important contributor and mechanistic basis for the development of pressure-overload induced cardiac hypertrophy.
BACKGROUND: Although both Gαq- and Gα11-protein signaling are believed to be involved in the regulation of cardiac hypertrophy, their detailed contribution to myocardial function remains elusive. METHODS AND RESULTS: We studied remodeling processes in healthy transgenic mice with genetically altered Gαq/Gα11-expression, in particular a global Gα11-knockout and a novel inducible cardiac specific Gαq-knockout, as well as a combined double knockout (dKO) mouse line. Echocardiography and telemetric ECG recordings revealed that compared with wild type mice, hearts of dKO mice showed an increased ejection fraction and a decreased heart rate, irrespective of age resulting in a maintained cardiac output. We attributed these findings to the lack of Gα11, which the absence was associated with a decreased afterload. Histological analysis of the extracellular matrix in the heart depicted a diminished presence of collagen in aging hearts of dKO mice compared to wild-type mice. The results of a transcriptome analysis on isolated ventricular cardiac myocytes revealed alterations of the activity of genes involved in the Gαq/Gα11-dependent regulation of the extracellular matrix, such as the matricellular protein Cyr61. CONCLUSIONS: From our data we conclude that Gαq/Gα11 signaling pathways play a pivotal role in maintaining gene activity patterns. For the heart we revealed their importance in modulating the properties of the extracellular matrix, a mechanism that might be an important contributor and mechanistic basis for the development of pressure-overload induced cardiac hypertrophy.
Authors: Elisabeth Kaiser; Qinghai Tian; Michael Wagner; Monika Barth; Wenying Xian; Laura Schröder; Sandra Ruppenthal; Lars Kaestner; Ulrich Boehm; Philipp Wartenberg; Huiyan Lu; Sara M McMillin; Derek B J Bone; Jürgen Wess; Peter Lipp Journal: Cardiovasc Res Date: 2019-05-01 Impact factor: 10.787