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Dietary quercetin improves endothelial function and protects against atherosclerosis in ApoE knockout mice fed a high-fat diet
Cardiovascular, Disorders II 6:
Metabolic
&
Environmental
Cardiovascular, Disorders II 7:
Metabolic
&
Environmental
Increased organ levels of angiotensin II in ren2 rats leads to the formation of reactive oxygen species and DNA damage
Dietary quercetin improves endothelial function and protects against atherosclerosis in ApoE knockout mice fed a high-fat diet
G. Fazeli*, H. Stopper, S. Weissenberger, C. Makiol, A. Heidland, N. Schupp University of Würzburg, Germany
Y. Shen1 ,3, N.C. Ward1, J.M. Hodgson1, Y. Wang2, R. Stocker2, K.D. Croft*1 1 University of Western Australia, Australia, 2University of Sydney, Australia, 3Nanjing University, Australia
A number of reports have indicated that activation of the renin-angiotensin-aldosterone system leads to the formation of reactive oxygen species (ROS). Epidemiological studies have revealed higher kidney cancer incidences and higher cancer mortalities in hypertensive individuals. Here, we report that in cell lines of kidney origin, angiotensin II (Ang II) causes ROS formation and DNA damaging activity which depend on an Ang II type 1 receptor-mediated activation of NADPH oxidase, with the NADPH isoform Nox4 playing a crucial role. To elucidate the impact of Ang II on the organs most affected by hypertension in vivo, the TGR(mREN2)27 (ren2) rat model was used which is characterized by elevated concentrations of Ang II in kidneys, heart and brain. Due to the severity of hypertension, the rats are kept under angiotensin converting enzyme inhibitor therapy with ramipril. Ramipril medication was withdrawn in a group of twelve week old ren2 rats for four weeks. These rats showed a significantly elevated blood pressure in comparison to the ramipril-treated ren2 rats and the wild type Sprague-Dawley (SD) rats. Renal function was significantly impaired in the untreated group in comparison to the ramipril-treated group and the SD rats as indicated by albumin to creatinine ratio. Formation of ROS and DNA double strand breaks were detected by dihydroethidium staining and gamma-H2AX in the kidney and the heart. ROS burden proved to be elevated in the kidney and heart of the untreated group. Increased numbers of DNA double strand breaks were found in the kidney of the untreated group. Further, these endpoints were investigated in the hippocampus of untreated and ramipril-treated ren2 and the results were compared to those from SD rats. The results of this study contribute to understanding of the mechanism of hypertension-related end organ damage. Keywords: Angiotensin II, Ren2 rats, hypertension, DNA damage doi:10.1016/j.freeradbiomed.2012.08.563
Introduction: Long and short term intervention studies using polyphenol-rich food, including fruit, cocoa, tea and red wine have shown cardiovascular protective effects. We investigated whether quercetin, an important polyphenol compound found in fruit and vegetables can improve endothelial function and attenuate atherosclerosis in mice fed a high fat diet. Methods & Results: WT and ApoE-/- mice were fed (a) high fat diet or (b) high fat diet supplemented with quercetin (0.05% w/w), for 14 weeks. Treatment with the quercetin-supplemented high-fat diet significantly attenuated oxidant-induced (hypochlorous acid) endothelial dysfunction in both the WT and ApoE-/- mice. Endothelium-dependent vasodilation was significantly improved by quercetin supplementation in WT mice. 24h urinary nitrite and NO synthase activity were significantly improved with quercetin treatment for both WT and ApoE-/- mice. HO-1 protein expression was increased in aortic tissue of quercetin fed mice. Plasma F2isoprostanes were elevated in apoE-/- mice compared to WT mice and were significantly reduced by dietary quercetin. Atherosclerotic lesions were significantly reduced (P<0.05) in apoE-/- mice fed the quercetinsupplemented diet. Quercetin was unable to protect against HOCl-induced endothelial dysfunction in arteries obtained from heterozygous HO-1 KO mice which have very low expression of HO-1 protein. This suggests that HO-1 expression is critical for the endothelail protective effects of quercetin. Discussion: Long term consumption of quercetin was able to improve endothelial function, particularly against oxidative stress, by improving NO bioavailability and inducing HO-1 in WT and ApoE-/- mice. Our results suggest that quercetin, a major dietary polyphenol compound may have potential cardio-protective effects that could be achieved through dietary consumption. Keywords: endothelial function, oxidative stress, polyphenol
atherosclerosis,
doi:10.1016/j.freeradbiomed.2012.08.564
S69
Metabolic
&
Environmental
Cardiovascular, Disorders II 7:
Metabolic
&
Environmental
Increased organ levels of angiotensin II in ren2 rats leads to the formation of reactive oxygen species and DNA damage
Dietary quercetin improves endothelial function and protects against atherosclerosis in ApoE knockout mice fed a high-fat diet
G. Fazeli*, H. Stopper, S. Weissenberger, C. Makiol, A. Heidland, N. Schupp University of Würzburg, Germany
Y. Shen1 ,3, N.C. Ward1, J.M. Hodgson1, Y. Wang2, R. Stocker2, K.D. Croft*1 1 University of Western Australia, Australia, 2University of Sydney, Australia, 3Nanjing University, Australia
A number of reports have indicated that activation of the renin-angiotensin-aldosterone system leads to the formation of reactive oxygen species (ROS). Epidemiological studies have revealed higher kidney cancer incidences and higher cancer mortalities in hypertensive individuals. Here, we report that in cell lines of kidney origin, angiotensin II (Ang II) causes ROS formation and DNA damaging activity which depend on an Ang II type 1 receptor-mediated activation of NADPH oxidase, with the NADPH isoform Nox4 playing a crucial role. To elucidate the impact of Ang II on the organs most affected by hypertension in vivo, the TGR(mREN2)27 (ren2) rat model was used which is characterized by elevated concentrations of Ang II in kidneys, heart and brain. Due to the severity of hypertension, the rats are kept under angiotensin converting enzyme inhibitor therapy with ramipril. Ramipril medication was withdrawn in a group of twelve week old ren2 rats for four weeks. These rats showed a significantly elevated blood pressure in comparison to the ramipril-treated ren2 rats and the wild type Sprague-Dawley (SD) rats. Renal function was significantly impaired in the untreated group in comparison to the ramipril-treated group and the SD rats as indicated by albumin to creatinine ratio. Formation of ROS and DNA double strand breaks were detected by dihydroethidium staining and gamma-H2AX in the kidney and the heart. ROS burden proved to be elevated in the kidney and heart of the untreated group. Increased numbers of DNA double strand breaks were found in the kidney of the untreated group. Further, these endpoints were investigated in the hippocampus of untreated and ramipril-treated ren2 and the results were compared to those from SD rats. The results of this study contribute to understanding of the mechanism of hypertension-related end organ damage. Keywords: Angiotensin II, Ren2 rats, hypertension, DNA damage doi:10.1016/j.freeradbiomed.2012.08.563
Introduction: Long and short term intervention studies using polyphenol-rich food, including fruit, cocoa, tea and red wine have shown cardiovascular protective effects. We investigated whether quercetin, an important polyphenol compound found in fruit and vegetables can improve endothelial function and attenuate atherosclerosis in mice fed a high fat diet. Methods & Results: WT and ApoE-/- mice were fed (a) high fat diet or (b) high fat diet supplemented with quercetin (0.05% w/w), for 14 weeks. Treatment with the quercetin-supplemented high-fat diet significantly attenuated oxidant-induced (hypochlorous acid) endothelial dysfunction in both the WT and ApoE-/- mice. Endothelium-dependent vasodilation was significantly improved by quercetin supplementation in WT mice. 24h urinary nitrite and NO synthase activity were significantly improved with quercetin treatment for both WT and ApoE-/- mice. HO-1 protein expression was increased in aortic tissue of quercetin fed mice. Plasma F2isoprostanes were elevated in apoE-/- mice compared to WT mice and were significantly reduced by dietary quercetin. Atherosclerotic lesions were significantly reduced (P<0.05) in apoE-/- mice fed the quercetinsupplemented diet. Quercetin was unable to protect against HOCl-induced endothelial dysfunction in arteries obtained from heterozygous HO-1 KO mice which have very low expression of HO-1 protein. This suggests that HO-1 expression is critical for the endothelail protective effects of quercetin. Discussion: Long term consumption of quercetin was able to improve endothelial function, particularly against oxidative stress, by improving NO bioavailability and inducing HO-1 in WT and ApoE-/- mice. Our results suggest that quercetin, a major dietary polyphenol compound may have potential cardio-protective effects that could be achieved through dietary consumption. Keywords: endothelial function, oxidative stress, polyphenol
atherosclerosis,
doi:10.1016/j.freeradbiomed.2012.08.564
S69