Parthenolide inhibits STAT3 signaling and attenuates angiotensin II-induced left ventricular hypertrophy via modulation of fibroblast activity

Réka Skoumal, Miklós Tóth, Raisa Serpi, Jaana Rysä, Hanna Leskinen, Johanna Ulvila, Tarja Saiho, Jani Aro, Heikki Ruskoaho, István Szokodi, Risto Kerkelä

Research output: Contribution to journalArticle

24 Citations (Scopus)

Abstract

Parthenolide has shown promise in treatment of various cancers via inhibition of the transcription factor signal transducer and activator of transcription 3 (STAT3). Activation of STAT3 has been observed in left ventricular hypertrophy (LVH); however, its exact role is not known. The aim of the study was to examine the effects of parthenolide on pressure overload-induced LVH in rats. Pressure overload was induced by angiotensin II (Ang II) infusion (33μg/kg/h) for 1 week in the presence or absence of parthenolide (0.5. mg/kg/day, i.p.). Ang II infusion resulted in LVH associated with increased phosphorylation of STAT3 at Tyr705 and Ser727. Parthenolide treatment had no effect on ejection fraction, but abolished the activation of STAT3 and reduced the Ang II-induced LVH (LV posterior wall thickness in end-diastole: 2.28 ± 0.12. mm vs. 1.80 ± 0.06. mm, P< 0.001). Importantly, parthenolide treatment had no effect on heart rate or blood pressure. Parthenolide treatment almost completely abolished the Ang II-induced increase in the number of cells positive for prolyl-4-hydroxylase, a marker for collagen-synthesizing cells, as well as Ang II-induced interstitial fibrosis in the left ventricles. This was associated with significant attenuation of Ang II-induced increase in mRNA levels of type 1 collagen and fibronectin. Moreover, parthenolide attenuated the Ang II-induced expression of interleukin-6, a potent pro-hypertrophic fibroblast-derived factor. We conclude that pharmacological inhibition of STAT3 signaling by parthenolide has favorable effects on pressure overload-induced LVH through attenuation of fibroblast activation. Therefore parthenolide may prove as a useful therapy for certain cardiovascular disease.

Original languageEnglish
Pages (from-to)634-641
Number of pages8
JournalJournal of Molecular and Cellular Cardiology
Volume50
Issue number4
DOIs
Publication statusPublished - Apr 1 2011

Keywords

  • Fibrosis
  • Left ventricular hypertrophy
  • Parthenolide
  • Pressure overload
  • STAT3

ASJC Scopus subject areas

  • Molecular Biology
  • Cardiology and Cardiovascular Medicine

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