1. Inhibition of TGF-β by a novel PPAR-γ agonist, chrysin, salvages β-receptor stimulated myocardial injury in rats through MAPKs-dependent mechanism.
- Author
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Rani, Neha, Bharti, Saurabh, Bhatia, Jagriti, Tomar, Ameesha, Nag, T. C., Ray, Ruma, and Arya, Dharamvir Singh
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HEART ventricles , *MYOCARDIAL infarction , *CORONARY heart disease prevention , *DNA , *ENZYME metabolism , *ALTERNATIVE medicine , *ANALYSIS of variance , *ANIMAL experimentation , *ANTI-inflammatory agents , *APOPTOSIS , *ARTERIES , *BIOPHYSICS , *BLOOD pressure , *CELLULAR signal transduction , *DOSE-effect relationship in pharmacology , *FLAVONOIDS , *GROWTH factors , *HEMODYNAMICS , *HISTOLOGICAL techniques , *IMMUNOHISTOCHEMISTRY , *LACTATE dehydrogenase , *RESEARCH methodology , *MICROSCOPY , *MYOCARDIUM , *NITRIC oxide , *PROBABILITY theory , *PROTEIN kinases , *RATS , *STAINS & staining (Microscopy) , *STATISTICS , *SUPEROXIDE dismutase , *TUMOR necrosis factors , *WESTERN immunoblotting , *DNA-binding proteins , *DATA analysis , *DATA analysis software , *PEROXISOME proliferator-activated receptors , *DESCRIPTIVE statistics , *PHYSIOLOGY - 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 27th and 28th 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. Conclusion: We established that activation of PPAR-γ and inhibition of TGF-β via MAPKs dependent mechanism is critical for cardioprotective effect of chrysin. [ABSTRACT FROM AUTHOR]
- Published
- 2015
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