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Hesperidin produces cardioprotective activity via PPAR-γ pathway in ischemic heart disease model in diabetic rats.

Agrawal YO, Sharma PK, Shrivastava B, Ojha S, Upadhya HM, Arya DS, Goyal SN - PLoS ONE (2014)

Bottom Line: Hesperidin pretreatment significantly improved mean arterial pressure, reduced left ventricular end-diastolic pressure, and improved both inotropic and lusitropic function of the heart (+LVdP/dt and -LVdP/dt) as compared to IR-control.Furthermore, hesperidin treatment significantly decreased the level of thiobarbituric acid reactive substances and reversed the activity of lactate dehydrogenase towards normal value.On the other hand, GW9662, selective PPAR-γ receptor antagonist, produced opposite effects and attenuated the hesperidin induced improvements.

View Article: PubMed Central - PubMed

Affiliation: School of Pharmaceutical Sciences, Jaipur National University, Jagatpura, Jaipur, Rajasthan, India; Department of Pharmacology, All India Institute of Medical Sciences, New Delhi, India; Department of Pharmaceutics and Pharmacology, R. C. Patel Institute of Pharmaceutical Education and Research, Shirpur, Maharashtra, India.

ABSTRACT
The present study investigated the effect of hesperidin, a natural flavonoid, in cardiac ischemia and reperfusion (I/R) injury in diabetic rats. Male Wistar rats with diabetes were divided into five groups and were orally administered saline once daily (IR-sham and IR-control), Hesperidin (100 mg/kg/day; IR-Hesperidin), GW9962 (PPAR-γ receptor antagonist), or combination of both for 14 days. On the 15th day, in the IR-control and IR-treatment groups, rats were subjected to left anterior descending (LAD) coronary artery occlusion for 45 minutes followed by a one-hour reperfusion. Haemodynamic parameters were recorded and rats were sacrificed; hearts were isolated for biochemical, histopathological, ultrastructural and immunohistochemistry. In the IR-control group, significant ventricular dysfunctions were observed along with enhanced expression of pro-apoptotic protein Bax. A decline in cardiac injury markers lactate dehydrogenase activity, CK-MB and increased content of thiobarbituric acid reactive substances, a marker of lipid peroxidation, and TNF-α were observed. Hesperidin pretreatment significantly improved mean arterial pressure, reduced left ventricular end-diastolic pressure, and improved both inotropic and lusitropic function of the heart (+LVdP/dt and -LVdP/dt) as compared to IR-control. Furthermore, hesperidin treatment significantly decreased the level of thiobarbituric acid reactive substances and reversed the activity of lactate dehydrogenase towards normal value. Hesperidin showed anti-apoptotic effects by upregulating Bcl-2 protein and decreasing Bax protein expression. Additionally, histopathological and ultrastructural studies reconfirmed the protective action of hesperidin. On the other hand, GW9662, selective PPAR-γ receptor antagonist, produced opposite effects and attenuated the hesperidin induced improvements. The study for the first time evidence the involvement of PPAR-γ pathway in the cardioprotective activity of hesperidin in I/R model in rats.

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Effect of hesperidin and GW9662 on mean arterial pressure (MAP) and left ventricular (LV) function following ischaemia/reperfusion (I/R) in diabetic rats.(A) MAP, (B) left ventricular end-diastolic pressure (LVEDP), (C) maximal positive rate of left ventricular pressure (+LVdP/dtmax) and (D) maximal negative rate of −LVdP/dtmax. Data are expressed as the mean ± standard error (n = 22/group). Significance was determined by repeated measures analysis of variance followed by the Bonferroni's post hoc test: *p<0.05, **p<0.001 vs Diabetic SHAM; #p<0.05, ##p <0.001 vs Diabetic I/R; $p<0.01 vs respective Hesperidin.
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pone-0111212-g002: Effect of hesperidin and GW9662 on mean arterial pressure (MAP) and left ventricular (LV) function following ischaemia/reperfusion (I/R) in diabetic rats.(A) MAP, (B) left ventricular end-diastolic pressure (LVEDP), (C) maximal positive rate of left ventricular pressure (+LVdP/dtmax) and (D) maximal negative rate of −LVdP/dtmax. Data are expressed as the mean ± standard error (n = 22/group). Significance was determined by repeated measures analysis of variance followed by the Bonferroni's post hoc test: *p<0.05, **p<0.001 vs Diabetic SHAM; #p<0.05, ##p <0.001 vs Diabetic I/R; $p<0.01 vs respective Hesperidin.

Mentions: The effects of hesperidin and GW9662 on haemodynamic and LV functions during I/R-induced MI in diabetic rats are depicted in Figure 2 (A–D). While significant decrease (p<0.001) was observed in the MAP and ±LVdP/dtmax, increased LVEDP was recorded in the rats subjected to cardiac I/R as compared to diabetic sham group. Fourteen days pretreatment with hesperidin significantly increased MAP, ±LVdP/dtmax and decreased LVEDP throughout I/R period at every time point, as compared to the diabetic I/R group. The dose of hesperidine (100 mg/kg/day for 14 days) was selected depending on the dose dependent study of hesperidine (data not shown). Hesperidine at 100 mg/kg produced significant results as compared to that of 50 and 200 mg/kg. Thus, 100 mg/kg dose was finalized for the entire work and administered to animals to study the effect of cardioprotection in rats. On the other hand pretreatment with GW9662 showed opposite effects as that of hesperidin and worsen the conditions as compared to that in the diabetic I/R group. Interestingly, pretreatment with GW9662 fifteen min prior to hesperidin significantly blocked the reversal effects of hesperidin in the diabetic I/R conditions for MAP, ±LVdP/dtmax and LVEDP throughout I/R period at every time point as compared to respective hesperidin treatment.


Hesperidin produces cardioprotective activity via PPAR-γ pathway in ischemic heart disease model in diabetic rats.

Agrawal YO, Sharma PK, Shrivastava B, Ojha S, Upadhya HM, Arya DS, Goyal SN - PLoS ONE (2014)

Effect of hesperidin and GW9662 on mean arterial pressure (MAP) and left ventricular (LV) function following ischaemia/reperfusion (I/R) in diabetic rats.(A) MAP, (B) left ventricular end-diastolic pressure (LVEDP), (C) maximal positive rate of left ventricular pressure (+LVdP/dtmax) and (D) maximal negative rate of −LVdP/dtmax. Data are expressed as the mean ± standard error (n = 22/group). Significance was determined by repeated measures analysis of variance followed by the Bonferroni's post hoc test: *p<0.05, **p<0.001 vs Diabetic SHAM; #p<0.05, ##p <0.001 vs Diabetic I/R; $p<0.01 vs respective Hesperidin.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4219710&req=5

pone-0111212-g002: Effect of hesperidin and GW9662 on mean arterial pressure (MAP) and left ventricular (LV) function following ischaemia/reperfusion (I/R) in diabetic rats.(A) MAP, (B) left ventricular end-diastolic pressure (LVEDP), (C) maximal positive rate of left ventricular pressure (+LVdP/dtmax) and (D) maximal negative rate of −LVdP/dtmax. Data are expressed as the mean ± standard error (n = 22/group). Significance was determined by repeated measures analysis of variance followed by the Bonferroni's post hoc test: *p<0.05, **p<0.001 vs Diabetic SHAM; #p<0.05, ##p <0.001 vs Diabetic I/R; $p<0.01 vs respective Hesperidin.
Mentions: The effects of hesperidin and GW9662 on haemodynamic and LV functions during I/R-induced MI in diabetic rats are depicted in Figure 2 (A–D). While significant decrease (p<0.001) was observed in the MAP and ±LVdP/dtmax, increased LVEDP was recorded in the rats subjected to cardiac I/R as compared to diabetic sham group. Fourteen days pretreatment with hesperidin significantly increased MAP, ±LVdP/dtmax and decreased LVEDP throughout I/R period at every time point, as compared to the diabetic I/R group. The dose of hesperidine (100 mg/kg/day for 14 days) was selected depending on the dose dependent study of hesperidine (data not shown). Hesperidine at 100 mg/kg produced significant results as compared to that of 50 and 200 mg/kg. Thus, 100 mg/kg dose was finalized for the entire work and administered to animals to study the effect of cardioprotection in rats. On the other hand pretreatment with GW9662 showed opposite effects as that of hesperidin and worsen the conditions as compared to that in the diabetic I/R group. Interestingly, pretreatment with GW9662 fifteen min prior to hesperidin significantly blocked the reversal effects of hesperidin in the diabetic I/R conditions for MAP, ±LVdP/dtmax and LVEDP throughout I/R period at every time point as compared to respective hesperidin treatment.

Bottom Line: Hesperidin pretreatment significantly improved mean arterial pressure, reduced left ventricular end-diastolic pressure, and improved both inotropic and lusitropic function of the heart (+LVdP/dt and -LVdP/dt) as compared to IR-control.Furthermore, hesperidin treatment significantly decreased the level of thiobarbituric acid reactive substances and reversed the activity of lactate dehydrogenase towards normal value.On the other hand, GW9662, selective PPAR-γ receptor antagonist, produced opposite effects and attenuated the hesperidin induced improvements.

View Article: PubMed Central - PubMed

Affiliation: School of Pharmaceutical Sciences, Jaipur National University, Jagatpura, Jaipur, Rajasthan, India; Department of Pharmacology, All India Institute of Medical Sciences, New Delhi, India; Department of Pharmaceutics and Pharmacology, R. C. Patel Institute of Pharmaceutical Education and Research, Shirpur, Maharashtra, India.

ABSTRACT
The present study investigated the effect of hesperidin, a natural flavonoid, in cardiac ischemia and reperfusion (I/R) injury in diabetic rats. Male Wistar rats with diabetes were divided into five groups and were orally administered saline once daily (IR-sham and IR-control), Hesperidin (100 mg/kg/day; IR-Hesperidin), GW9962 (PPAR-γ receptor antagonist), or combination of both for 14 days. On the 15th day, in the IR-control and IR-treatment groups, rats were subjected to left anterior descending (LAD) coronary artery occlusion for 45 minutes followed by a one-hour reperfusion. Haemodynamic parameters were recorded and rats were sacrificed; hearts were isolated for biochemical, histopathological, ultrastructural and immunohistochemistry. In the IR-control group, significant ventricular dysfunctions were observed along with enhanced expression of pro-apoptotic protein Bax. A decline in cardiac injury markers lactate dehydrogenase activity, CK-MB and increased content of thiobarbituric acid reactive substances, a marker of lipid peroxidation, and TNF-α were observed. Hesperidin pretreatment significantly improved mean arterial pressure, reduced left ventricular end-diastolic pressure, and improved both inotropic and lusitropic function of the heart (+LVdP/dt and -LVdP/dt) as compared to IR-control. Furthermore, hesperidin treatment significantly decreased the level of thiobarbituric acid reactive substances and reversed the activity of lactate dehydrogenase towards normal value. Hesperidin showed anti-apoptotic effects by upregulating Bcl-2 protein and decreasing Bax protein expression. Additionally, histopathological and ultrastructural studies reconfirmed the protective action of hesperidin. On the other hand, GW9662, selective PPAR-γ receptor antagonist, produced opposite effects and attenuated the hesperidin induced improvements. The study for the first time evidence the involvement of PPAR-γ pathway in the cardioprotective activity of hesperidin in I/R model in rats.

Show MeSH
Related in: MedlinePlus