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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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Photomicrograph of myocardial tissue sections showing Bcl-2 (A–E), Bax proteins expression (F–J) and TUNEL-positive cells (K–O).Apoptotic nuclei are indicated by arrows in panels (×400). (A, F and K) represents Diabetic sham rats treated with vehicles, (B, G and L) diabetic ischaemia/reperfusion (I/R) rats treated with vehicles, (C, H and M) diabetic I/R rats treated with hesperidin, (D, I and N) diabetic I/R rats treated with GW9662 and (E, J and O) diabetic I/R rats treated with GW9662 and hesperidin. (P) represents the quantitative analysis of the Bcl-2, Bax proteins and TUNEL-positive cells in the different groups. Data are expressed as the mean ± standard error (n = 6). *p<0.05, *p<0.001 vs diabetic SHAM; #p<0.05, ##p<0.001 vs Diabetic I/R group; @p<0.01 vs Diabetic I/R + hesperidin.
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pone-0111212-g005: Photomicrograph of myocardial tissue sections showing Bcl-2 (A–E), Bax proteins expression (F–J) and TUNEL-positive cells (K–O).Apoptotic nuclei are indicated by arrows in panels (×400). (A, F and K) represents Diabetic sham rats treated with vehicles, (B, G and L) diabetic ischaemia/reperfusion (I/R) rats treated with vehicles, (C, H and M) diabetic I/R rats treated with hesperidin, (D, I and N) diabetic I/R rats treated with GW9662 and (E, J and O) diabetic I/R rats treated with GW9662 and hesperidin. (P) represents the quantitative analysis of the Bcl-2, Bax proteins and TUNEL-positive cells in the different groups. Data are expressed as the mean ± standard error (n = 6). *p<0.05, *p<0.001 vs diabetic SHAM; #p<0.05, ##p<0.001 vs Diabetic I/R group; @p<0.01 vs Diabetic I/R + hesperidin.

Mentions: To confirm the involvement of PPAR-γ receptors in the cardioprotection by Hesperidin, the estimation of apoptosis regulatory proteins (Bax and Bcl-2) using immunohistopathological studies were conducted in the diabetic sham and diabetic I/R rats treated with vehicle, hesperidin and GW9662 either alone or in combination. Photomicrographs in the Figure 5 (A-E), (F-J) and (K-O) shows the effect of hesperidin and GW9662 either alone or in combination on Bcl-2, Bax proteins and TUNEL positive cells, respectively, in the diabetic I/R rats and Figure 5P represents the quantitative analysis of the same. While significant decrease in Bcl-2 was observed (B), Bax proteins and TUNEL positive cells were significantly increased in the diabetic I/R rats (G and L) as compared to diabetic sham control (A, F and K). On the other hand, hesperidin treatment significantly prevented the changes in Bcl-2 and Bax proteins and TUNEL positive cells as observed in the Diabetic I/R group (C, H and M). In contrast to this, GW9662 treatment exaggerated the diabetic I/R induced conditions (D, I and N), and also attenuated the hesperidin induced effects with respect to the Bcl-2 and Bax proteins, and TUNEL positive cells (E, J and O).


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)

Photomicrograph of myocardial tissue sections showing Bcl-2 (A–E), Bax proteins expression (F–J) and TUNEL-positive cells (K–O).Apoptotic nuclei are indicated by arrows in panels (×400). (A, F and K) represents Diabetic sham rats treated with vehicles, (B, G and L) diabetic ischaemia/reperfusion (I/R) rats treated with vehicles, (C, H and M) diabetic I/R rats treated with hesperidin, (D, I and N) diabetic I/R rats treated with GW9662 and (E, J and O) diabetic I/R rats treated with GW9662 and hesperidin. (P) represents the quantitative analysis of the Bcl-2, Bax proteins and TUNEL-positive cells in the different groups. Data are expressed as the mean ± standard error (n = 6). *p<0.05, *p<0.001 vs diabetic SHAM; #p<0.05, ##p<0.001 vs Diabetic I/R group; @p<0.01 vs Diabetic I/R + hesperidin.
© Copyright Policy
Related In: Results  -  Collection

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pone-0111212-g005: Photomicrograph of myocardial tissue sections showing Bcl-2 (A–E), Bax proteins expression (F–J) and TUNEL-positive cells (K–O).Apoptotic nuclei are indicated by arrows in panels (×400). (A, F and K) represents Diabetic sham rats treated with vehicles, (B, G and L) diabetic ischaemia/reperfusion (I/R) rats treated with vehicles, (C, H and M) diabetic I/R rats treated with hesperidin, (D, I and N) diabetic I/R rats treated with GW9662 and (E, J and O) diabetic I/R rats treated with GW9662 and hesperidin. (P) represents the quantitative analysis of the Bcl-2, Bax proteins and TUNEL-positive cells in the different groups. Data are expressed as the mean ± standard error (n = 6). *p<0.05, *p<0.001 vs diabetic SHAM; #p<0.05, ##p<0.001 vs Diabetic I/R group; @p<0.01 vs Diabetic I/R + hesperidin.
Mentions: To confirm the involvement of PPAR-γ receptors in the cardioprotection by Hesperidin, the estimation of apoptosis regulatory proteins (Bax and Bcl-2) using immunohistopathological studies were conducted in the diabetic sham and diabetic I/R rats treated with vehicle, hesperidin and GW9662 either alone or in combination. Photomicrographs in the Figure 5 (A-E), (F-J) and (K-O) shows the effect of hesperidin and GW9662 either alone or in combination on Bcl-2, Bax proteins and TUNEL positive cells, respectively, in the diabetic I/R rats and Figure 5P represents the quantitative analysis of the same. While significant decrease in Bcl-2 was observed (B), Bax proteins and TUNEL positive cells were significantly increased in the diabetic I/R rats (G and L) as compared to diabetic sham control (A, F and K). On the other hand, hesperidin treatment significantly prevented the changes in Bcl-2 and Bax proteins and TUNEL positive cells as observed in the Diabetic I/R group (C, H and M). In contrast to this, GW9662 treatment exaggerated the diabetic I/R induced conditions (D, I and N), and also attenuated the hesperidin induced effects with respect to the Bcl-2 and Bax proteins, and TUNEL positive cells (E, J and O).

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