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ADVERSE EFFECTS OF HIGH GLUCOSE AND FREE FATTY ACID ON CARDIOMYOCYTES ARE MEDIATED BY CONNECTIVE TISSUE GROWTH FACTOR.

Authors: Wang, XY  MCLennan, SV  Allen, T  Tsoutsman, T  Semsarian, C  Twigg, SM 
Citation: Wang XY, etal., Am J Physiol Cell Physiol. 2009 Jul 22.
Pubmed: (View Article at PubMed) PMID:19625611
DOI: Full-text: DOI:10.1152/ajpcell.00049.2009

AIMS/HYPOTHESIS: 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. METHODS: Hearts from STZ 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. RESULTS: Each reagent induced cell hypertrophy, as indicated by the ratio of total protein /cell number, cell size and gene expression of cardiac hypertrophy marker genes ANP and alpha-skeletal actin. Each treatment also caused apoptosis, measured by increased caspase3/7 activity, apoptotic cells by 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. SiRNA against CTGF blocked the high glucose and palmitate induction of hypertrophy and apoptosis. In addition, these CTGF effects were through the TrkA receptor with tyrosine kinase activity, which has previously been implicated in CTGF signalling: TrkA was phosphorylated by CTGF and a specific TrkA blocker abrogated CTGF-induced effects on hypertrophy and apoptosis. CONCLUSIONS/INTERPRETATION: 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. Key words: diabetes, cardiac myocytes, hypertrophy, growth factors.

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CRRD Object Information
CRRD ID: 2314487
Created: 2009-11-17
Species: All species
Last Modified: 2009-11-17
Status: ACTIVE



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RGD is funded by grant HL64541 from the National Heart, Lung, and Blood Institute on behalf of the NIH.