In vivo cardiac role of migfilin during experimental pressure overload

• Published in: Cardiovascular research 2015-06, Vol.106 (3), p.398-407
• Main Authors: Haubner, Bernhard Johannes, Moik, Daniel, Schuetz, Thomas, Reiner, Martin F, Voelkl, Jakob G, Streil, Katrin, Bader, Kerstin, Zhao, Lei, Scheu, Claudia, Mair, Johannes, Pachinger, Otmar, Metzler, Bernhard
• Format: Article
• Language: English
• Subjects: Active Transport, Cell Nucleus; Animals; Cell Adhesion Molecules - deficiency; Cell Adhesion Molecules - genetics; Cell Adhesion Molecules - metabolism; Disease Models, Animal; Enzyme Activation; Extracellular Signal-Regulated MAP Kinases - metabolism; Fibrosis; Heart Failure - genetics; Heart Failure - metabolism; Heart Failure - physiopathology; Hypertension - complications; Hypertension - physiopathology; Hypertrophy, Left Ventricular - genetics; Hypertrophy, Left Ventricular - metabolism; Hypertrophy, Left Ventricular - pathology; Hypertrophy, Left Ventricular - physiopathology; Hypertrophy, Left Ventricular - prevention & control; Male; Mice, Inbred C57BL; Mice, Knockout; Myocytes, Cardiac - metabolism; Myocytes, Cardiac - pathology; Proto-Oncogene Proteins c-akt - metabolism; Signal Transduction; Time Factors; Ventricular Remodeling
• ISSN: 0008-6363; 1755-3245
• DOI: 10.1093/cvr/cvv125

Increased myocardial wall strain triggers the cardiac hypertrophic response by increasing cardiomyocyte size, reprogramming gene expression, and enhancing contractile protein synthesis. The LIM protein, migfilin, is a cytoskeleton-associated protein that was found to translocate in vitro into the nucleus in a Ca(2+)-dependent manner, where it co-activates the pivotal cardiac transcription factor Csx/Nkx2.5. However, the in vivo role of migfilin in cardiac function and stress response is unclear. To define the role of migfilin in cardiac hypertrophy, we induced hypertension by transverse aortic constriction (TAC) and compared cardiac morphology and function of migfilin knockout (KO) with wild-type (WT) hearts. Heart size and myocardial contractility were comparable in untreated migfilin KO and WT hearts, but migfilin-null hearts presented a reduced extent of hypertrophic remodelling in response to chronic hypertensile stress. Migfilin KO mice maintained their cardiac function for a longer time period compared with WT mice, which presented extensive fibrosis and death due to heart failure. Migfilin translocated into the nucleus of TAC-treated cardiomyocytes, and migfilin KO hearts showed reduced Akt activation during the early response to pressure overload. Our findings indicate an important role of migfilin in the regulation of cardiac hypertrophy upon experimental TAC.