Abstract
Fatty acid binding protein 4 (FABP4) is a member of the intracellular lipid-binding protein family, responsible for the transportation of fatty acids. It is considered to express mainly in adipose tissues, and be strongly associated with inflammation, obesity, diabetes and cardiovasculardiseases. Here we report that FABP4 is also expressed in cardiomyocytes and plays an important role in regulating heart function under pressure overload. We generated heart-specific transgenic FABP4 (FABP4-TG) mice using α myosin-heavy chain (α-MHC) promoter and human FABP4 sequence, resulting in over-expression of FABP4 in cardiomyocytes. The FABP4-TG mice displayed normal cardiac morphology and contractile function. When they were subjected to the transverse aorta constriction (TAC) procedure, the FABP4-TG mice developed more cardiac hypertrophy correlated with significantly increased ERK phosphorylation, compared with wild type controls. FABP4 over-expression in cardiomyocytes activated phosphor-ERK signal and up-regulate the expression of cardiac hypertrophic marker genes. Conversely, FABP4 induced phosphor-ERK signal and hypertrophic gene expressions can be markedly inhibited by an ERK inhibitor PD098059 as well as the FABP4 inhibitor BMS309403. These results suggest that FABP4 over-expression in cardiomyocytes can aggravate the development of cardiac hypertrophy through the activation of ERK signal pathway.
Highlights
Cardiac hypertrophy, the thickening of heart muscle, is a compensatory response to physical stimuli or pathological insults in heart
To determine whether Fatty acid binding protein 4 (FABP4) is expressed in cardiomyocytes, we first cultured neonatal rat cardiac myocytes (NRCMs) and transfected a Flag-tagged-PPARγ expression plasmid into NRCMs to test if FABP4 expression can be detected in cardiomyocytes and further regulated by over-expressing PPARγ
Cardiomyocytes has a much higher level of FABP4 expression than cardiac fibroblast (Figure B in S1 Fig). These results indicate that FABP4 is expressed in cardiomyocytes and can be regulated by PPARγ, suggesting FABP4 may have potential important roles in cardiac metabolism and functions
Summary
The thickening of heart muscle, is a compensatory response to physical stimuli or pathological insults in heart. The energy expenditure and the structure of cardiomyocyte will change, and heart will utilize glucose instead of fatty acids as the main source of energy. These processes are mediated by stress-responsive and other signaling pathways [1,2,3,4,5,6]. Lipids and lipid related proteins are critical in the heart metabolism and play significant parts in cardiac hypertrophy development Both over-expressing [9] and knock-out PPARγ[10] in mice heart can induce lipid disorder and leads to cardiac hypertrophy. Compared with other FABPs, the adipocyte FABP, commonly known as FABP4 or AP2 (Adipocyte Protein 2), is highly expressed in adipocyte and has multiple functions other than fatty acid transportation
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