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Inhibition of TGF-β by a novel PPAR-γ agonist, chrysin, salvages β-receptor stimulated myocardial injury in rats through MAPKs-dependent mechanism.

Rani N, Bharti S, Bhatia J, Tomar A, Nag TC, Ray R, Arya DS - Nutr Metab (Lond) (2015)

Bottom Line: 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.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.We established that activation of PPAR-γ and inhibition of TGF-β via MAPKs dependent mechanism is critical for cardioprotective effect of chrysin.

View Article: PubMed Central - PubMed

Affiliation: Department of Pharmacology, All India Institute of Medical Sciences, New Delhi, 110029 India.

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.

Conclusion: We established that activation of PPAR-γ and inhibition of TGF-β via MAPKs dependent mechanism is critical for cardioprotective effect of chrysin.

No MeSH data available.


Related in: MedlinePlus

Effect of chrysin on MAPKs protein expressions following isoproterenol-induced myocardial injury. (a) ERK½ and P-ERK½; (b) JNK and P-JNK; (c) p38 and P-p38 and (d) MMP-2. All values for protein expressions are expressed as mean ± S.D (n = 3/group). #P < 0.01, *P < 0.001 vs. sham and §P < 0.05, †P < 0.001 vs. ISO.
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Fig6: Effect of chrysin on MAPKs protein expressions following isoproterenol-induced myocardial injury. (a) ERK½ and P-ERK½; (b) JNK and P-JNK; (c) p38 and P-p38 and (d) MMP-2. All values for protein expressions are expressed as mean ± S.D (n = 3/group). #P < 0.01, *P < 0.001 vs. sham and §P < 0.05, †P < 0.001 vs. ISO.

Mentions: Furthermore, to establish the potential role of chrysin on cell differentiation and survival, we studied protein expressions of MMP-2 and MAPKs pathway involving ERK½, P-ERK½, p38, P-p38, JNK, and P-JNK (Figure 6a-d). Intriguingly, we found that rats fed with chrysin augmented P-ERK½ to ERK½ protein expression ratio and attenuated P-p38 to p38 and P-JNK to JNK protein expression ratio and MMP-2 protein expression at 30 and 60 mg/kg but the effect was more significant (P < 0.001) at the highest dose following isoproterenol-induced myocardial injury (Figures 6a-d).Figure 6


Inhibition of TGF-β by a novel PPAR-γ agonist, chrysin, salvages β-receptor stimulated myocardial injury in rats through MAPKs-dependent mechanism.

Rani N, Bharti S, Bhatia J, Tomar A, Nag TC, Ray R, Arya DS - Nutr Metab (Lond) (2015)

Effect of chrysin on MAPKs protein expressions following isoproterenol-induced myocardial injury. (a) ERK½ and P-ERK½; (b) JNK and P-JNK; (c) p38 and P-p38 and (d) MMP-2. All values for protein expressions are expressed as mean ± S.D (n = 3/group). #P < 0.01, *P < 0.001 vs. sham and §P < 0.05, †P < 0.001 vs. ISO.
© Copyright Policy - open-access
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4359541&req=5

Fig6: Effect of chrysin on MAPKs protein expressions following isoproterenol-induced myocardial injury. (a) ERK½ and P-ERK½; (b) JNK and P-JNK; (c) p38 and P-p38 and (d) MMP-2. All values for protein expressions are expressed as mean ± S.D (n = 3/group). #P < 0.01, *P < 0.001 vs. sham and §P < 0.05, †P < 0.001 vs. ISO.
Mentions: Furthermore, to establish the potential role of chrysin on cell differentiation and survival, we studied protein expressions of MMP-2 and MAPKs pathway involving ERK½, P-ERK½, p38, P-p38, JNK, and P-JNK (Figure 6a-d). Intriguingly, we found that rats fed with chrysin augmented P-ERK½ to ERK½ protein expression ratio and attenuated P-p38 to p38 and P-JNK to JNK protein expression ratio and MMP-2 protein expression at 30 and 60 mg/kg but the effect was more significant (P < 0.001) at the highest dose following isoproterenol-induced myocardial injury (Figures 6a-d).Figure 6

Bottom Line: 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.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.We established that activation of PPAR-γ and inhibition of TGF-β via MAPKs dependent mechanism is critical for cardioprotective effect of chrysin.

View Article: PubMed Central - PubMed

Affiliation: Department of Pharmacology, All India Institute of Medical Sciences, New Delhi, 110029 India.

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.

Conclusion: We established that activation of PPAR-γ and inhibition of TGF-β via MAPKs dependent mechanism is critical for cardioprotective effect of chrysin.

No MeSH data available.


Related in: MedlinePlus