Heparin and heparan sulfate inhibit extracellular signal-regulated kinase activation and myocardial cell hypertrophy induced by endothelin-1

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Heparan sulfate (HS) is one of the components of extracellular matrix and apotent antigrowth factor in various cells. Heparin has a similar structure to HS andis demonstrated to inhibit myocardial cell hypertrophy. We examined theintracellular signal mechanisms linking to the inhibitory effects of heparin and HSon endothelin-1(ET-1)-induced hypertrophy in cultured rat neonatal myocardial cells(MCs). Heparin inhibited ET-1-induced c-fos mRNA expression. Heparin and HSinhibited ET-1-induced activation of c-fos promoter/enhancer in MCs. Althoughheparin and HS inhibited ET-1-induced activation of the wild-type c-fos serumresponse element (SRE), the activation of a mutated c-fos SRE that contains anintact binding site for the serum response factor (SRF) but lacks the ternary complexfactor (TCF) binding site, was not inhibited. In addition, heparin and HS inhibitedthe activation of TPA response element (TRE). However, heparin did not inhibit the activation of cyclic AMP responseelement (CRE). Furthermore, heparin and HS inhibited ET-1-induced activation ofextracellular signal-regulated kinase (ERK) and phosphorylation of Elk-1 , which isone of the TCFs. These results indicate that heparin and HS inhibited ET-1-inducedERK activation, resulting in suppression of Elk-1 phosphorylation, and lead toinhibition of c-fos gene expression through SRF-independent manner. Moreover,heparin and HS inhibited ET-1-induced [3H] Ieucine incorporation. These resultssuggest that heparin and HS inhibit ET-1 induced myocardial cell hypertrophythrough the inhibition of gene expression and protein synthesis.
神戸大学の論文

Heparin and heparan sulfate inhibit extracellular signal-regulated kinase activation and myocardial cell hypertrophy induced by endothelin-1

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