Limits...
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.

Show MeSH

Related in: MedlinePlus

Photomicrograph showing the ultrastructural changes in the rat myocardium.(A) represents transmission electron microscope [(TEM) ×4800] in diabetic sham group, B diabetic ischaemia/reperfusion (I/R) group (TEM ×3500), (C) diabetic I/R + hesperidin treatment (100 mg/kg) (TEM ×3500), (D) diabetic I/R + GW9662 (1 mg/kg) (TEM ×3500) and (E) diabetic I/R rats + GW9662 + hesperidin (TEM ×3500).
© Copyright Policy
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC4219710&req=5

pone-0111212-g004: Photomicrograph showing the ultrastructural changes in the rat myocardium.(A) represents transmission electron microscope [(TEM) ×4800] in diabetic sham group, B diabetic ischaemia/reperfusion (I/R) group (TEM ×3500), (C) diabetic I/R + hesperidin treatment (100 mg/kg) (TEM ×3500), (D) diabetic I/R + GW9662 (1 mg/kg) (TEM ×3500) and (E) diabetic I/R rats + GW9662 + hesperidin (TEM ×3500).

Mentions: As shown in Figure 4A, diabetic sham rats showed well preserved mitochondrial structure and glycogen granules throughout the myocardium. Significant disruption of the myofibrils, myonecrosis, depletion of the glycogen reserves, swollen and irregular mitochondria with a loss of cristae and chromatin condensation was observed in the diabetic I/R rats (Figure 4B). On the other hand, hesperidin treatment showed only a mild separation of the mitochondrial cristae without swelling and vacuolation (Figure 4C). More severe ultrastructural complications in conjunction with severe peripheral nuclear condensation were observed in the GW9662-treated group as compared to diabetes I/R rats (Figure 4D). In addition, GW9662 treatment prior to hesperidin blocked the recovery process of hesperidin per se (Figure 4E).


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 showing the ultrastructural changes in the rat myocardium.(A) represents transmission electron microscope [(TEM) ×4800] in diabetic sham group, B diabetic ischaemia/reperfusion (I/R) group (TEM ×3500), (C) diabetic I/R + hesperidin treatment (100 mg/kg) (TEM ×3500), (D) diabetic I/R + GW9662 (1 mg/kg) (TEM ×3500) and (E) diabetic I/R rats + GW9662 + hesperidin (TEM ×3500).
© Copyright Policy
Related In: Results  -  Collection

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

pone-0111212-g004: Photomicrograph showing the ultrastructural changes in the rat myocardium.(A) represents transmission electron microscope [(TEM) ×4800] in diabetic sham group, B diabetic ischaemia/reperfusion (I/R) group (TEM ×3500), (C) diabetic I/R + hesperidin treatment (100 mg/kg) (TEM ×3500), (D) diabetic I/R + GW9662 (1 mg/kg) (TEM ×3500) and (E) diabetic I/R rats + GW9662 + hesperidin (TEM ×3500).
Mentions: As shown in Figure 4A, diabetic sham rats showed well preserved mitochondrial structure and glycogen granules throughout the myocardium. Significant disruption of the myofibrils, myonecrosis, depletion of the glycogen reserves, swollen and irregular mitochondria with a loss of cristae and chromatin condensation was observed in the diabetic I/R rats (Figure 4B). On the other hand, hesperidin treatment showed only a mild separation of the mitochondrial cristae without swelling and vacuolation (Figure 4C). More severe ultrastructural complications in conjunction with severe peripheral nuclear condensation were observed in the GW9662-treated group as compared to diabetes I/R rats (Figure 4D). In addition, GW9662 treatment prior to hesperidin blocked the recovery process of hesperidin per se (Figure 4E).

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