Cardiac Fibroblast Glycogen Synthase Kinase-3β Regulates Ventricular Remodeling and Dysfunction in Ischemic Heart

• Published in: Circulation (New York, N.Y.) Vol. 130; no. 5; pp. 419 - 430
• Main Authors: HIND LAL, AHMAD, Firdos, FORCE, Thomas, JIBIN ZHOU, YU, Justine E, VAGNOZZI, Ronald J, YUANJUN GUO, DAOHAI YU, TSAI, Emily J, WOODGETT, James, GAO, Erhe
• Format: Journal Article
• Language: English
• Published: Hagerstown, MD Lippincott Williams & Wilkins 29.07.2014
• Subjects: Aged; Animals; Biological and medical sciences; Blood and lymphatic vessels; Cardiology. Vascular system; Coronary heart disease; Diseases of the peripheral vessels. Diseases of the vena cava. Miscellaneous; Enzyme Activation - physiology; Extracellular Matrix - metabolism; Fibroblasts - cytology; Fibroblasts - enzymology; Fibrosis - metabolism; Fibrosis - pathology; Glycogen Synthase Kinase 3 - genetics; Glycogen Synthase Kinase 3 - metabolism; Glycogen Synthase Kinase 3 beta; Heart; Humans; Male; Medical sciences; Mice, Knockout; Middle Aged; Myocardial Ischemia - metabolism; Myocardial Ischemia - pathology; Myocarditis. Cardiomyopathies; Myocardium - cytology; Myocardium - enzymology; Primary Cell Culture; RNA, Small Interfering - genetics; Smad3 Protein - metabolism; Ventricular Dysfunction, Left - metabolism; Ventricular Dysfunction, Left - pathology; Ventricular Remodeling - physiology; Heart; Myocardial infarction; Enzyme; Glycogen; Transferases; Cardiovascular disease; Synthase; Coronary heart disease; Myocardial disease; Vascular remodeling; Regulation(control); fibroblasts; Ischemia; Glycogen synthase kinase-3β; Kinase; Dysfunction; Fibrosis; glycogen synthase kinase 3 beta; Circulatory system; Cardiology; Fibroblast; Hypertrophy; fibrosis; hypertrophy; myocardial infarction
• ISSN: 0009-7322; 1524-4539
• DOI: 10.1161/CIRCULATIONAHA.113.008364

Myocardial infarction-induced remodeling includes chamber dilatation, contractile dysfunction, and fibrosis. Of these, fibrosis is the least understood. After myocardial infarction, activated cardiac fibroblasts deposit extracellular matrix. Current therapies to prevent fibrosis are inadequate, and new molecular targets are needed. Herein we report that glycogen synthase kinase-3β (GSK-3β) is phosphorylated (inhibited) in fibrotic tissues from ischemic human and mouse heart. Using 2 fibroblast-specific GSK-3β knockout mouse models, we show that deletion of GSK-3β in cardiac fibroblasts leads to fibrogenesis, left ventricular dysfunction, and excessive scarring in the ischemic heart. Deletion of GSK-3β induces a profibrotic myofibroblast phenotype in isolated cardiac fibroblasts, in post-myocardial infarction hearts, and in mouse embryonic fibroblasts deleted for GSK-3β. Mechanistically, GSK-3β inhibits profibrotic transforming growth factor-β1/SMAD-3 signaling via interactions with SMAD-3. Moreover, deletion of GSK-3β resulted in the significant increase of SMAD-3 transcriptional activity. This pathway is central to the pathology because a small-molecule inhibitor of SMAD-3 largely prevented fibrosis and limited left ventricular remodeling. These studies support targeting GSK-3β in myocardial fibrotic disorders and establish critical roles of cardiac fibroblasts in remodeling and ventricular dysfunction.