title: Inhibition of TGF-β by a novel PPAR-γ agonist, chrysin, salvages β-receptor stimulated myocardial injury in rats through MAPKs-dependent mechanism.
abstract: BACKGROUND
  Pharmacological stimulation of peroxisome proliferator-activated receptor-gamma (PPAR-γ) has been recognized as a molecular switch in alleviating myocardial injury through modulating oxidative, inflammatory and apoptotic signaling pathways. This study was designed to elucidate the effect of chrysin, a novel PPAR-γ agonist and its functional interaction with TGF-β/MAPKs in isoproterenol-challenged myocardial injury in rats.
  
  
  METHODS
  Male Wistar Albino rats were either subjected to vehicle (1.5 mL/kg, p.o.) or chrysin (15-60 mg/kg, p.o.) for 28 days. Isoproterenol (85 mg/kg, s.c.) was administered to rats on 27(th) and 28(th) day to induce myocardial injury.
  
  
  RESULTS
  Chrysin dose dependently improved ventricular (±LVdP/dtmax and LVEDP) and hemodynamic (SAP, MAP and DAP) dysfunction in isoproterenol-insulted rats. This beneficial effect of chrysin was well supported with increased expression of PPAR-γ and decreased expression of TGF-β as evidenced by western blotting and immunohistochemistry analysis. Moreover, downstream signaling pathway of TGF-β viz. P-ERK½/ERK½ activation and P-JNK/JNK, P-p38/p38 and MMP-2 inhibition were also observed. Chrysin also attenuated NF-κBp65 and IKK-β expressions, TNF-α level and TUNEL positivity thereby validating its anti-inflammatory and anti-apoptotic properties. Additionally, chrysin in a dose dependent fashion improved NO level, redox status of the myocardium (GSH and MDA levels and SOD, GSHPx and CAT activities), cardiac injury markers (CK-MB and LDH levels) and oxidative DNA damage marker (8-OHdG level) and displayed preservation of subcellular and ultrastructural components.
  
  
  CONCLUSIONS
  We established that activation of PPAR-γ and inhibition of TGF-β via MAPKs dependent mechanism is critical for cardioprotective effect of chrysin.
authors.affiliation: Department of Pharmacology, All India Institute of Medical Sciences, New Delhi, 110029 India.
authors.forename: Neha
authors.initials: N
authors.lastname: Rani
authors.affiliation: Department of Pharmacology, All India Institute of Medical Sciences, New Delhi, 110029 India.
authors.forename: Saurabh
authors.initials: S
authors.lastname: Bharti
authors.affiliation: Department of Pharmacology, All India Institute of Medical Sciences, New Delhi, 110029 India.
authors.forename: Jagriti
authors.initials: J
authors.lastname: Bhatia
authors.affiliation: Department of Pharmacology, All India Institute of Medical Sciences, New Delhi, 110029 India.
authors.forename: Ameesha
authors.initials: A
authors.lastname: Tomar
authors.affiliation: Department of Anatomy, All India Institute of Medical Sciences, New Delhi, 110029 India.
authors.forename: T C
authors.initials: TC
authors.lastname: Nag
authors.affiliation: Department of Pathology, All India Institute of Medical Sciences, New Delhi, 110029 India.
authors.forename: Ruma
authors.initials: R
authors.lastname: Ray
authors.affiliation: Department of Pharmacology, All India Institute of Medical Sciences, New Delhi, 110029 India.
authors.forename: Dharamvir Singh
authors.initials: DS
authors.lastname: Arya
keywords: Chrysin; Isoproterenol; MAPKs; Myocardial injury; PPAR-γ; TGF-β