title: Heparin and heparan sulfate inhibit extracellular signal-regulated kinase activation and myocardial cell hypertrophy induced by endothelin-1.
abstract: Heparan sulfate (HS) is one of the components of extracellular matrix and a potent anti-growth factor in various cells. Heparin has a similar structure to HS and is demonstrated to inhibit myocardial cell hypertrophy. We examined the intracellular signal mechanisms linking to the inhibitory effects of heparin and HS on endothelin-1 (ET-1)-induced hypertrophy in cultured rat neonatal myocardial cells (MCs). Heparin inhibited ET-1-induced c-fos mRNA expression. Heparin and HS inhibited ET-1-induced activation of c-fos promoter/enhancer in MCs. Although heparin and HS inhibited ET-1-induced activation of the wild-type c-fos serum response element (SRE), the activation of a mutated c-fos SRE that contains an intact binding site for the serum response factor (SRF) but lacks the ternary complex factor (TCF) binding site, was not inhibited. In addition, heparin and HS inhibited the activation of TPA response element (TRE). However, heparin did not inhibit the activation of cyclic AMP response element (CRE). Furthermore, heparin and HS inhibited ET-1-induced activation of extracellular signal-regulated kinase (ERK) and phosphorylation of Elk-1, which is one of the TCFs. These results indicate that heparin and HS inhibited ET-1-induced ERK activation, resulting in suppression of Elk-1 phosphorylation, and lead to inhibition of c-fos gene expression through SRF-independent manner. Moreover, heparin and HS inhibited ET-1-induced [3H] leucine incorporation. These results suggest that heparin and HS inhibit ET-1 induced myocardial cell hypertrophy through the inhibition of gene expression and protein synthesis.
authors.affiliation: Division of Surgical Pathology, Division of Cardiovascular and Respiratory Internal Medicine, Kobe University Graduate School of Medicine.
authors.forename: K
authors.initials: K
authors.lastname: Mizutani
authors.forename: S
authors.initials: S
authors.lastname: Kawashima
authors.forename: T
authors.initials: T
authors.lastname: Ueyama
authors.forename: T
authors.initials: T
authors.lastname: Sakoda
authors.forename: S
authors.initials: S
authors.lastname: Takeuchi
authors.forename: S
authors.initials: S
authors.lastname: Kobayashi
authors.forename: M
authors.initials: M
authors.lastname: Yokoyama
authors.forename: Y
authors.initials: Y
authors.lastname: Hayashi
authors.forename: H
authors.initials: H
authors.lastname: Itoh
mesh_terms: D000596:Amino Acids / Q000378:metabolism; D000818:Animals; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism; D004268:DNA-Binding Proteins; D019332:Endothelin-1 / Q000494:pharmacology*; D004742:Enhancer Elements, Genetic; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D015870:Gene Expression / Q000187:drug effects; D006493:Heparin / Q000494:pharmacology*; D006497:Heparan Sulfate / Q000494:pharmacology*; D006984:Hypertrophy; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors*; D009206:Myocardium / Q000378:metabolism / Q000473:pathology*; D010766:Phosphorylation; D011401:Promoter Regions, Genetic; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D016760:Proto-Oncogene Proteins c-fos / Q000235:genetics; D012333:RNA, Messenger / Q000235:genetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D020218:Response Elements; D014157:Transcription Factors; D050807:ets-Domain Protein Elk-1
chemical_list: D000596:Amino Acids; D017362:Cyclic AMP Response Element-Binding Protein; D004268:DNA-Binding Proteins; D019332:Endothelin-1; D004791:Enzyme Inhibitors; D006493:Heparin; D006497:Heparan Sulfate; D020928:Mitogen-Activated Protein Kinases; D011518:Proto-Oncogene Proteins; D016760:Proto-Oncogene Proteins c-fos; D012333:RNA, Messenger; D014157:Transcription Factors; D050807:ets-Domain Protein Elk-1; C494114:Elk1 protein, rat