Adverse effects of high glucose and free fatty acid on cardiomyocytes are mediated by connective tissue growth factor

• Published in: American Journal of Physiology: Cell Physiology Vol. 297; no. 6; pp. C1490 - C1500
• Main Authors: Wang, Xiaoyu, McLennan, Susan V, Allen, Terri J, Tsoutsman, Tatiana, Semsarian, Christopher, Twigg, Stephen M
• Format: Journal Article
• Language: English
• Published: United States American Physiological Society 01.12.2009
• Subjects: Animals; Animals, Newborn; Apoptosis; Cardiomegaly - etiology; Cell culture; Cell growth; Cell Size - drug effects; Cells, Cultured; Connective Tissue Growth Factor - metabolism; Connective Tissue Growth Factor - pharmacology; Diabetes; Diabetes Mellitus, Experimental - complications; Diabetes Mellitus, Experimental - metabolism; Diabetes Mellitus, Experimental - pathology; Diabetes Mellitus, Experimental - physiopathology; Dose-Response Relationship, Drug; Fatty acids; Gene expression; Glucose; Glucose - administration & dosage; Humans; Hypertrophy; Male; Mice; Mice, Inbred C57BL; Myocardium - pathology; Myocytes, Cardiac - drug effects; Myocytes, Cardiac - metabolism; Myocytes, Cardiac - pathology; Palmitates - pharmacology; Rats; Rats, Sprague-Dawley; Receptor, trkA - metabolism; Recombinant Proteins - pharmacology; Rodents; Tissues
• ISSN: 0363-6143; 1522-1563
• DOI: 10.1152/ajpcell.00049.2009

1 Endocrinology Research Laboratories and the 2 Discipline of Medicine, The University of Sydney, Sydney; 3 Department of Endocrinology, Royal Prince Alfred Hospital, Sydney; 4 Baker Heart and Diabetes Research Institute, Melbourne; and 5 Agnes Ginges Centre for Molecular Cardiology, Centenary Institute and 6 Department of Cardiology, Royal Prince Alfred Hospital, Sydney, Australia Submitted 27 January 2009 ; accepted in final form 21 July 2009 Diabetic cardiomyopathy is characterized by interstitial fibrosis and cardiomyocyte hypertrophy and apoptosis. Also known as CCN2, connective tissue growth factor (CTGF) is implicated in the fibrosis; however, whether it contributes to cardiomyocytes changes and adverse effects of high glucose and lipids on these cells remains unknown. Hearts from streptozotocin-induced diabetic rats had elevated CTGF and changes of pathological myocardial hypertrophy, fibrosis, and cardiomyocyte apoptosis. Rat H9c2 cardiomyocytes were then treated with recombinant human (rh)CTGF, high glucose, or the saturated free fatty acid palmitate. Each reagent induced cell hypertrophy, as indicated by the ratio of total protein to cell number, cell size, and gene expression of cardiac hypertrophy marker genes atrial natriuretic peptide (ANP), and -skeletal actin. Each treatment also caused apoptosis measured by increased caspase3/7 activity, apoptotic cells by transferase-mediated dUTP nick end labeling (TUNEL) assay, and lower viable cell number. Further studies showed CTGF mRNA was rapidly induced by high glucose and palmitate in H9c2 cells and in mouse neonatal cardiomyocyte primary cultures. small interfering RNA against CTGF blocked the high glucose and palmitate induction of hypertrophy and apoptosis. In addition, these CTGF effects were through the tyrosine kinase A (TrkA) receptor with tyrosine kinase activity, which has previously been implicated in CTGF signaling: TrkA was phosphorylated by CTGF, and a specific TrkA blocker abrogated CTGF-induced effects on hypertrophy and apoptosis. For the first time in any system, fatty acid is newly identified as a regulator of CTGF, and this work implicates autocrine CTGF as a mediator of adverse effects of high glucose and fatty acids in cardiomyocytes. diabetic cardiomyopathy; apoptosis; hypertrophy Address for reprint requests and other correspondence: S. M. Twigg, Discipline of Medicine, The Univ. of Sydney, Endocrinologist and Head of Endocrinology Research Laboratories, Royal Prince Alfred Hospital, Sydney, NSW 2006, Australia (e-mail: stwigg{at}med.usyd.edu.au ).