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Please use this identifier to cite or link to this item: http://hdl.handle.net/1946/11967

  • Anti-TGF-β effects of telmisartan occurs independent of the angiotensin II receptor
  • June 2012
  • Introduction: Mitral valve prolapse (MVP) is the most common cardiac valve abnormality in the industrialized world. Dysregulation of TGF-β signaling has been implicated in myxomatous degeneration where valvular interstitial cells (VIC) appear to play a primary role. Angiotensin receptor blockers (ARB) are primarily pharmacological target for angiotensin II receptor type 1 (AT1) but ARBs also modulate TGF-β signaling through an uncharacterized mechanism. ARB such as telmisartan can induce peroxisome proliferator-activated receptor (PPAR)-γ activity but known PPAR-γ agonists have also been shown to modulate TGF-β signaling. Our hypothesis is that telmisartan modulates TGF-β signaling through PPAR-γ independently of AT1.
    Materials and methods: Operative specimens were obtained from 8 MVP patients undergoing mitral valve repair. VICs were isolated and propagated. Immunofluorescence, western blotting and quantitative real time PCR were used in the experiments to evaluate the anti-TGF-β effects of telmisartan.
    Results: The VICs were positive for vimentin, SM22α and α-smooth muscle actin compared to smooth muscle cells (SMC). The same cells were negative for angiotensin II receptors type 1 and type 2 (AT1 and AT2) compared to SMCs and fibroblasts. The TGF-β activated p38 but had no effect on the activation on JNK-1 or PI3K, which were constitutively active. Telmisartan significantly decreased TGF-β induced collagen 1 (COL1A1) and elastin (ELN) expression in the VICs and the PPAR-γ agonist, PGJ2, did the same. However, the PPAR-γ antagonist GW9962 did not inhibit the anti-TGF-beta effects of telmisartan on COL1A1 and ELN expression. The PPAR-γ agonist pioglitazone did not significantly decrease TGF-β induced COL1A1 and ELN expression. TGF-β activated Smad2 independently of telmisartan and AT1. The ERK and p38 signaling pathways appeared to be activated by telmisartan but independent of AT1.
    Conclusion: TGF-beta activates Smad2 and p38 in cultured VIC and induces extracellular matrix expression. VICs do not bind angiotensin II possibly due to absence of AT1 and AT2. Telmisartan effectively inhibits TGF-beta signaling independent of AT1, which appears to occur through PPAR-γ, but needs further verification.

  • is Unnið að hluta til við Section of Cardiac Surgery, Yale University School of Medicine
  • Jun 4, 2012
  • http://hdl.handle.net/1946/11967

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