The myocardium of the failing heart undergoes a number of structural 
alterations, most notably hypertrophy of cardiac myocytes and an increase in 
extracellular matrix proteins, often seen as primary fibrosis. Connective tissue 
growth factor (CTGF) is a key molecule in the process of fibrosis and therefore 
seems an attractive therapeutic target. Regulation of CTGF expression at the 
promoter level has been studied extensively, but it is unknown how CTGF 
transcripts are regulated at the posttranscriptional level. Here we provide 
several lines of evidence to show that CTGF is importantly regulated by 2 major 
cardiac microRNAs (miRNAs), miR-133 and miR-30. First, the expression of both 
miRNAs was inversely related to the amount of CTGF in 2 rodent models of heart 
disease and in human pathological left ventricular hypertrophy. Second, in 
cultured cardiomyocytes and fibroblasts, knockdown of these miRNAs increased 
CTGF levels. Third, overexpression of miR-133 or miR-30c decreased CTGF levels, 
which was accompanied by decreased production of collagens. Fourth, we show that 
CTGF is a direct target of these miRNAs, because they directly interact with the 
3' untranslated region of CTGF. Taken together, our results indicate that 
miR-133 and miR-30 importantly limit the production of CTGF. We also provide 
evidence that the decrease of these 2 miRNAs in pathological left ventricular 
hypertrophy allows CTGF levels to increase, which contributes to collagen 
synthesis. In conclusion, our results show that both miR-133 and miR-30 directly 
downregulate CTGF, a key profibrotic protein, and thereby establish an important 
role for these miRNAs in the control of structural changes in the extracellular 
matrix of the myocardium.