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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 hemodynamic parameters following isoproterenol-induced myocardial injury. (a) SAP: Systolic arterial pressure; (b) DAP: Diastolic arterial Pressure; (c) MAP: Mean arterial pressure; (d) + LVdP/dtmax: Maximal positive rate of left ventricular pressure; (e) -LVdP/dtmax: Maximal negative rate of left ventricular pressure; (f) LVEDP: Left ventricular end diastolic pressure and (g) HR: Heart rate. All values are expressed as mean ± S.D (n = 10/group).*P < 0.001 vs. sham and §P < 0.05, αP < 0.01, †P < 0.001 vs. ISO.
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Fig1: Effect of chrysin on hemodynamic parameters following isoproterenol-induced myocardial injury. (a) SAP: Systolic arterial pressure; (b) DAP: Diastolic arterial Pressure; (c) MAP: Mean arterial pressure; (d) + LVdP/dtmax: Maximal positive rate of left ventricular pressure; (e) -LVdP/dtmax: Maximal negative rate of left ventricular pressure; (f) LVEDP: Left ventricular end diastolic pressure and (g) HR: Heart rate. All values are expressed as mean ± S.D (n = 10/group).*P < 0.001 vs. sham and §P < 0.05, αP < 0.01, †P < 0.001 vs. ISO.

Mentions: To investigate the ability of chrysin to alleviate cardiac functions we evaluated its effect on hemodynamic and ventricular assessments. Isoproterenol administration resulted in significant (P < 0.001) hemodynamic impairment in rats as observed through significantly reduced SAP, DAP and MAP as compared to sham group (Figure 1a-c). Similarly, significant (P < 0.001) ventricular dysfunction was also observed as exhibited through decreased contractility (+LVdP/dtmax), relaxation (−LVdP/dtmax) and increased LVEDP (Figure 1d-f). Interestingly, chrysin (15–60 mg/kg) dose dependently abolished the detrimental effect of isoproterenol and improved hemodynamic and ventricular dysfunction as observed by significant (P < 0.01) improvement in arterial pressures, ±LVdP/dtmax and LVEDP, though the level of significance (P < 0.001) was found to be greater with the highest dose (60 mg/kg) as compared to other two doses (Figure 1a-f). No significant change in HR was observed in any of the groups (Figure 1g).Figure 1


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 hemodynamic parameters following isoproterenol-induced myocardial injury. (a) SAP: Systolic arterial pressure; (b) DAP: Diastolic arterial Pressure; (c) MAP: Mean arterial pressure; (d) + LVdP/dtmax: Maximal positive rate of left ventricular pressure; (e) -LVdP/dtmax: Maximal negative rate of left ventricular pressure; (f) LVEDP: Left ventricular end diastolic pressure and (g) HR: Heart rate. All values are expressed as mean ± S.D (n = 10/group).*P < 0.001 vs. sham and §P < 0.05, αP < 0.01, †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

Fig1: Effect of chrysin on hemodynamic parameters following isoproterenol-induced myocardial injury. (a) SAP: Systolic arterial pressure; (b) DAP: Diastolic arterial Pressure; (c) MAP: Mean arterial pressure; (d) + LVdP/dtmax: Maximal positive rate of left ventricular pressure; (e) -LVdP/dtmax: Maximal negative rate of left ventricular pressure; (f) LVEDP: Left ventricular end diastolic pressure and (g) HR: Heart rate. All values are expressed as mean ± S.D (n = 10/group).*P < 0.001 vs. sham and §P < 0.05, αP < 0.01, †P < 0.001 vs. ISO.
Mentions: To investigate the ability of chrysin to alleviate cardiac functions we evaluated its effect on hemodynamic and ventricular assessments. Isoproterenol administration resulted in significant (P < 0.001) hemodynamic impairment in rats as observed through significantly reduced SAP, DAP and MAP as compared to sham group (Figure 1a-c). Similarly, significant (P < 0.001) ventricular dysfunction was also observed as exhibited through decreased contractility (+LVdP/dtmax), relaxation (−LVdP/dtmax) and increased LVEDP (Figure 1d-f). Interestingly, chrysin (15–60 mg/kg) dose dependently abolished the detrimental effect of isoproterenol and improved hemodynamic and ventricular dysfunction as observed by significant (P < 0.01) improvement in arterial pressures, ±LVdP/dtmax and LVEDP, though the level of significance (P < 0.001) was found to be greater with the highest dose (60 mg/kg) as compared to other two doses (Figure 1a-f). No significant change in HR was observed in any of the groups (Figure 1g).Figure 1

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