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Novel mechanisms of valsartan on the treatment of acute myocardial infarction through inhibition of the antiadhesion molecule periostin.

Abstract
Our previous study demonstrated that periostin, an extracellular matrix protein, plays an important role in left ventricular remodeling through the inhibition of cell-cell interactions. Because the gene regulation of periostin has not yet been examined, we focused on the effects of angiotensin (Ang) II and mechanical stretch, because Ang II and mechanical stretch are related to cardiac remodeling after myocardial infarction. First, we examined the effects of Ang II on periostin in myocytes and fibroblasts in vitro. Ang II significantly increased periostin through phosphatidylinositol 3-kinase, c-Jun N-terminal kinase, p38, and extracellular signal-regulated kinase 1/2 pathways in myocytes and fibroblasts (P<0.05). On the other hand, mechanical stretch also significantly increased periostin expression (P<0.05). This increase was inhibited partially, but significantly, by an Ang II receptor blocker, valsartan, and inhibited almost completely by valsartan with the neutralization antibodies for transforming growth factor-beta and platelet-derived growth factor-BB (P<0.05). Therefore, we further examined periostin expression in vivo. Periostin expression was significantly increased in infarcted myocardium (P<0.05), and treatment with valsartan significantly attenuated it at 4 weeks after myocardial infarction (P<0.05), accompanied by a significant improvement in cardiac dysfunction (P<0.05). Overall, the present study demonstrated that Ang II, as well as mechanical stretch, stimulated periostin expression in both cardiac myocytes and fibroblasts, whereas valsartan significantly attenuated the increase in periostin expression. The inhibition of periostin by valsartan might especially contribute to its beneficial effects on cardiac remodeling after myocardial infarction.
AuthorsKazuma Iekushi, Yoshiaki Taniyama, Junya Azuma, Naruto Katsuragi, Norio Dosaka, Fumihiro Sanada, Nobutaka Koibuchi, Kaori Nagao, Toshio Ogihara, Ryuichi Morishita
JournalHypertension (Dallas, Tex. : 1979) (Hypertension) Vol. 49 Issue 6 Pg. 1409-14 (Jun 2007) ISSN: 1524-4563 [Electronic] United States
PMID17485602 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References
  • Antihypertensive Agents
  • Cell Adhesion Molecules
  • Postn protein, rat
  • Tetrazoles
  • Angiotensin II
  • Valsartan
  • Valine
Topics
  • Acute Disease
  • Angiotensin II (physiology)
  • Animals
  • Antihypertensive Agents (pharmacology)
  • Cell Adhesion Molecules (antagonists & inhibitors, metabolism)
  • Cell Communication (physiology)
  • Cells, Cultured
  • Disease Models, Animal
  • Fibroblasts (drug effects, metabolism)
  • Gene Expression Regulation (drug effects)
  • Male
  • Myocardial Infarction (drug therapy, metabolism, physiopathology)
  • Myocardium (metabolism, pathology)
  • Myocytes, Cardiac (drug effects, metabolism)
  • Random Allocation
  • Rats
  • Rats, Inbred Lew
  • Rats, Wistar
  • Stress, Mechanical
  • Tetrazoles (pharmacology)
  • Valine (analogs & derivatives, pharmacology)
  • Valsartan
  • Ventricular Remodeling (physiology)

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