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Shokei Kimmitsuyama - One of the best experts on this subject based on the ideXlab platform.
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glycemic control with empagliflozin a novel selective sglt2 inhibitor ameliorates Cardiovascular Injury and cognitive dysfunction in obese and type 2 diabetic mice
Cardiovascular Diabetology, 2014Co-Authors: Bowen Lin, Nobutaka Koibuchi, Yu Hasegawa, Daisuke Sueta, Kensuke Toyama, Ken Uekawa, Ming Jie, Takashi Nakagawa, Hiroaki Kusaka, Shokei KimmitsuyamaAbstract:There has been uncertainty regarding the benefit of glycemic control with antidiabetic agents in prevention of diabetic macrovascular disease. Further development of novel antidiabetic agents is essential for overcoming the burden of diabetic macrovascular disease. The renal sodium glucose co-transporter 2 (SGLT2) inhibitor is a novel antihyperglycemic agent for treatment of type 2 diabetes. This work was performed to determine whether empagliflozin, a novel SGLT2 inhibitor, can ameliorate Cardiovascular Injury and cognitive decline in db/db mouse, a model of obesity and type 2 diabetes. (1) Short-term experiment: The first experiment was performed to examine the effect of 7 days of empagliflozin treatment on urinary glucose excretion and urinary electrolyte excretion in db/db mice. (2) Long-term experiment: The second experiment was undertaken to examine the effect of 10 weeks of empagliflozin treatment on Cardiovascular Injury, vascular dysfunction, cognitive decline, and renal Injury in db/db mice. (1) Short-term experiment: Empagliflozin administration significantly increased urinary glucose excretion, urine volume, and urinary sodium excretion in db/db mice on day 1, but did not increase these parameters from day 2. However, blood glucose levels in db/db mice were continuously decreased by empagliflozin throughout 7 days of the treatment. (2) Long-term experiment: Empagliflozin treatment caused sustained decrease in blood glucose in db/db mice throughout 10 weeks of the treatment and significantly slowed the progression of type 2 diabetes. Empagliflozin significantly ameliorated cardiac interstitial fibrosis, pericoronary arterial fibrosis, coronary arterial thickening, cardiac macrophage infiltration, and the impairment of vascular dilating function in db/db mice, and these beneficial effects of empagliflozin were associated with attenuation of oxidative stress in Cardiovascular tissue of db/db mice. Furthermore, empagliflozin significantly prevented the impairment of cognitive function in db/db mice, which was associated with the attenuation of cerebral oxidative stress and the increase in cerebral brain-derived neurotrophic factor. Empagliflozin ameliorated albuminuria, and glomerular Injury in db/db mice. Glycemic control with empagliflozin significantly ameliorated Cardiovascular Injury and remodeling, vascular dysfunction, and cognitive decline in obese and type 2 diabetic mice. Thus, empagliflozin seems to be potentially a promising therapeutic agent for diabetic macrovascular disease and cognitive decline.
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olmesartan prevents Cardiovascular Injury and hepatic steatosis in obesity and diabetes accompanied by apoptosis signal regulating kinase 1 inhibition
Hypertension, 2008Co-Authors: Eiichiro Yamamoto, Keiichiro Kataoka, Takuro Yamashita, Yoshiko Tokutomi, Yi Fei Dong, Shinji Matsuba, Hisao Ogawa, Hidenori Ichijo, Shokei KimmitsuyamaAbstract:Dietary obesity is associated with type 2 diabetes and Cardiovascular diseases, although the underlying mechanism is unknown. This study was undertaken to elucidate the role of angiotensin II and apoptosis signal regulating kinase-1 (ASK1) in obesity/diabetes-associated Cardiovascular complications and hepatic steatosis. Mice fed a high-fat diet were treated with olmesartan, an angiotensin II type 1 receptor blocker, to elucidate the role of angiotensin II in diabetic mice. Treatment of mice fed a high-fat diet with olmesartan markedly suppressed cardiac inflammation and fibrosis, as well as vascular endothelial dysfunction and remodeling, induced by obesity/diabetes. Moreover, olmesartan suppressed the disruption of the vascular endothelial NO synthase dimer in diabetic mice. Olmesartan also significantly prevented hepatic steatosis and fibrosis in diabetic mice. These beneficial effects of olmesartan on diabetic mice were associated with the attenuation of ASK1 activation in these mice. ASK1-deficient mice and wild-type mice were compared, regarding the effects of a high-fat diet. A comparison between ASK1-deficient and wild-type mice showed that ASK1 deficiency attenuated cardiac inflammation and fibrosis, as well as vascular endothelial dysfunction and remodeling induced by obesity/diabetes. The amelioration of vascular endothelial impairment by ASK1 deficiency was attributed to the prevention of endothelial NO synthase dimer disruption. ASK1 deficiency also significantly lessened hepatic steatosis in diabetic mice. In conclusion, our work provided the evidence that ASK1 is significantly activated in diet-induced diabetic mice and contributes to Cardiovascular diseases and hepatic steatosis in diabetic mice. Moreover, the beneficial effects of angiotensin II inhibition on dietary diabetic mice seem to be mediated by the inhibition of ASK1 activation.
Marina Politi Okoshi - One of the best experts on this subject based on the ideXlab platform.
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Cardiovascular changes in patients with non-severe Plasmodium vivax malaria ☆
IJC Heart & Vasculature, 2016Co-Authors: Aristoteles Comte Alencar-filho, Wuelton Marcelo Monteiro, João Marcos Bemfica Barbosa Ferreira, Jorge L. Salinas, Camila Fabbri, André M. Siqueira, Katashi Okoshi, Marcus Vinícius Guimarães Lacerda, Marina Politi OkoshiAbstract:Background Cardiovascular system involvement in patients with Plasmodium vivax malaria has been poorly addressed. The aim of this study was to evaluate cardiac structures and function, and serum markers of Cardiovascular Injury in patients with the non-severe form of vivax malaria in Manaus, Amazonas State, Brazil.
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Cardiovascular changes in patients with non-severe Plasmodium vivax malaria
IJC Heart & Vasculature, 2016Co-Authors: Aristoteles Comte Alencar-filho, Wuelton Marcelo Monteiro, João Marcos Bemfica Barbosa Ferreira, Jorge L. Salinas, Camila Fabbri, Katashi Okoshi, Marcus Vinícius Guimarães Lacerda, André Siqueira, Marina Politi OkoshiAbstract:Background Cardiovascular system involvement in patients with Plasmodium vivax malaria has been poorly addressed. The aim of this study was to evaluate cardiac structures and function, and serum markers of Cardiovascular Injury in patients with the non-severe form of vivax malaria in Manaus, Amazonas State, Brazil.
Keiichiro Kataoka - One of the best experts on this subject based on the ideXlab platform.
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long term renal denervation normalizes disrupted blood pressure circadian rhythm and ameliorates Cardiovascular Injury in a rat model of metabolic syndrome
Journal of the American Heart Association, 2013Co-Authors: Tetsuji Katayama, Nobutaka Koibuchi, Yu Hasegawa, Daisuke Sueta, Kensuke Toyama, Ken Uekawa, Takashi Nakagawa, Keiichiro Kataoka, Ma Mingjie, Masanobu MaedaAbstract:Background-—Although renal denervation significantly reduces blood pressure in patients with resistant hypertension, the role of the renal nerve in hypertension with metabolic syndrome is unknown. We investigated the impact of long-term renal denervation on SHR/NDmcr-cp(+/+) (SHRcp) rats, a useful rat model of metabolic syndrome, to determine the role of the renal nerve in hypertension with metabolic syndrome. Methods and Results-—SHRcp rats were divided into (1) a renal denervation (RD) group and (2) a sham operation group (control) to examine the effects of long-term RD on blood pressure circadian rhythm, renal sodium retention-related molecules, the renin-angiotensin-aldosterone system, metabolic disorders, and organ Injury. RD in SHRcp rats not only significantly reduced blood pressure but also normalized blood pressure circadian rhythm from the nondipper to the dipper type, and this improvement was associated with an increase in urinary sodium excretion and the suppression of renal Na + -Cl cotransporter upregulation. RD significantly reduced plasma renin activity. RD significantly prevented Cardiovascular remodeling and impairment of vascular endothelial function and attenuated Cardiovascular oxidative stress. However, RD failed to ameliorate obesity, metabolic disorders, and renal Injury and failed to reduce systemic sympathetic activity in SHRcp rats. Conclusions-—By including the upregulation of the Na + -Cl cotransporter, the renal sympathetic nerve is involved in the disruption of blood pressure circadian rhythm as well as hypertension in metabolic syndrome. Thus, RD seems to be a useful therapeutic strategy for hypertension with metabolic syndrome. (J Am Heart Assoc. 2013;2:e000197 doi: 10.1161/JAHA.113.000197)
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Eplerenone potentiates protective effects of amlodipine against Cardiovascular Injury in salt-sensitive hypertensive rats.
Hypertension Research, 2011Co-Authors: Taishi Nakamura, Eiichiro Yamamoto, Keiichiro Kataoka, Yoshiko Tokutomi, Yi Fei Dong, Hisao Ogawa, Masaya Fukuda, Hisato Nako, Osamu Yasuda, Shokei Kim-mitsuyamaAbstract:The clinical value of the combination of amlodipine and eplerenone is unclear. This study was undertaken to test whether eplerenone potentiates the protective effects of amlodipine against hypertensive Cardiovascular Injury. Salt-loaded Dahl salt-sensitive hypertensive rats (DS rats) were given (1) vehicle, (2) an antihypertensive dose of amlodipine, (3) a non-antihypertensive dose of eplerenone or (4) combined amlodipine and eplerenone for 6 weeks, and the effects on Cardiovascular injuries were compared. There was no significant difference among the four groups regarding plasma aldosterone, urine volume or urinary electrolytes. A subpressor dose of eplerenone markedly ameliorated vascular endothelial dysfunction, cardiac inflammation and fibrosis in DS rats to a similar degree as an antihypertensive dose of amlodipine. Addition of eplerenone to amlodipine, without affecting blood pressure, enhanced the improvement by amlodipine of vascular endothelial function, cardiac inflammation, fibrosis and diastolic dysfunction in DS rats. Additive beneficial effects of eplerenone were attributed to additive potentiation of eNOS and Akt phosphorylation and additive reduction of oxidative stress. Eplerenone significantly attenuated Cardiovascular NADPH oxidase activity by reducing gp91phox upregulation and attenuated the upregulation of Cardiovascular AT1 receptor, but amlodipine failed to affect them. Thus, the normalization by eplerenone of gp91phox and AT1 receptor upregulation seems to be at least partially responsible for the additive benefits of eplerenone in the prevention of hypertensive Cardiovascular Injury. The combination of amlodipine and eplerenone may be a promising therapeutic strategy for Cardiovascular disease in salt-sensitive hypertension.
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Apoptosis signal-regulating kinase 1 deficiency eliminates Cardiovascular injuries induced by high-salt diet.
Journal of Hypertension, 2011Co-Authors: Keiichiro Kataoka, Taishi Nakamura, Eiichiro Yamamoto, Yoshiko Tokutomi, Yi Fei Dong, Hisao Ogawa, Masaya Fukuda, Hidenori Ichijo, Shokei Kim-mitsuyamaAbstract:Objectives High-salt diet is closely associated with the increase in Cardiovascular events. However, the mechanism of high-salt-induced Cardiovascular Injury is unknown. The present study was undertaken to test our hypothesis that apoptosis signal-regulating kinase (ASK) 1 may be involved in salt-induced Cardiovascular Injury. Methods Wild-type and ASK1−/− mice were fed a low-salt or a high-salt diet for 10 weeks and the effects of high-salt diet on food intake, urinary volume and electrolyte excretion, and Cardiovascular Injury were compared between both groups of mice. Results High-salt diet in wild-type and ASK1−/− mice similarly increased food intake, water intake, urine volume, and urinary sodium excretion, and comparably decreased plasma renin activity and aldosterone. Thus, ASK1 appears to play a minor role in the increase in natriuresis and the decrease in plasma renin, and aldosterone caused by high-salt diet. High-salt diet enhanced the phosphorylation of Cardiovascular ASK1 in wild-type mice. High-salt diet in wild-type mice enhanced cardiac transforming growth factor-β1, interstitial fibrosis, coronary perivascular fibrosis, and inflammatory cell infiltration, and these changes were associated with the increase in cardiac superoxide and Nox2. ASK1 deficiency abolished the above-mentioned high-salt-induced cardiac Injury. High-salt diet also caused the impairment of vascular endothelium-dependent relaxation by acetylcholine and increased vascular superoxide, and Nox2 in wild-type mice, whereas it did not cause vascular Injury in ASK1−/− mice. Conclusion ASK1 is implicated in cardiac inflammation and fibrosis, and vascular endothelial dysfunction caused by high-salt diet, through the enhancement of oxidative stress.
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Ezetimibe Ameliorates Cardiovascular Complications and Hepatic Steatosis in Obese and Type 2 Diabetic db/db Mice
Journal of Pharmacology and Experimental Therapeutics, 2010Co-Authors: Masaya Fukuda, Taishi Nakamura, Keiichiro Kataoka, Yoshiko Tokutomi, Yi Fei Dong, Hisao Ogawa, Hisato Nako, Osamu Yasuda, Shokei Kim-mitsuyamaAbstract:Type 2 diabetes plays a major role in the development of Cardiovascular diseases. The present study was undertaken to investigate the effect of ezetimibe, a potent cholesterol absorption inhibitor, on Cardiovascular Injury of obese and type 2 diabetic db/db mice. Diabetic db/db mice fed western diet were given ezetimibe for 9 weeks and the effects on Cardiovascular Injury and hepatic steatosis were examined. Ezetimibe treatment of db/db mice significantly improved vascular endothelial function, which was associated with the restoration of the decreased phospho-Akt and phospho-eNOS. Moreover, ezetimibe also reduced vascular superoxide levels in db/db mice, accompanied by the attenuation of NADPH oxidase subunit gp91phox and Nox4, and the prevention of downregulation of Cu/Zn-SOD and EC-SOD. Thus, the improvement of vascular endothelial function by ezetimibe in diabetic mice seems to be attributed to the improvement of eNOS function and the attenuation of oxidative stress. Ezetimibe treatment also significantly attenuated cardiac interstitial fibrosis and coronary arterial thickening of diabetic mice and ameliorated cardiac macrophage infiltration. This improvement of cardiac Injury was also related to the attenuation of NADPH oxidase-mediated oxidative stress. Furthermore, ezetimibe significantly prevented hepatic steatosis, inflammation, and oxidative stress in diabetic mice. Our work provided the first evidence that ezetimibe prevented Cardiovascular Injury and hepatic steatosis in diabetic mice and these beneficial effects were attributed to the attenuation of oxidative stress and inflammation and the improvement of eNOS function. Therefore, we propose that ezetimibe may be a promising therapeutic drug for obese and type 2 diabetes.
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olmesartan prevents Cardiovascular Injury and hepatic steatosis in obesity and diabetes accompanied by apoptosis signal regulating kinase 1 inhibition
Hypertension, 2008Co-Authors: Eiichiro Yamamoto, Keiichiro Kataoka, Takuro Yamashita, Yoshiko Tokutomi, Yi Fei Dong, Shinji Matsuba, Hisao Ogawa, Hidenori Ichijo, Shokei KimmitsuyamaAbstract:Dietary obesity is associated with type 2 diabetes and Cardiovascular diseases, although the underlying mechanism is unknown. This study was undertaken to elucidate the role of angiotensin II and apoptosis signal regulating kinase-1 (ASK1) in obesity/diabetes-associated Cardiovascular complications and hepatic steatosis. Mice fed a high-fat diet were treated with olmesartan, an angiotensin II type 1 receptor blocker, to elucidate the role of angiotensin II in diabetic mice. Treatment of mice fed a high-fat diet with olmesartan markedly suppressed cardiac inflammation and fibrosis, as well as vascular endothelial dysfunction and remodeling, induced by obesity/diabetes. Moreover, olmesartan suppressed the disruption of the vascular endothelial NO synthase dimer in diabetic mice. Olmesartan also significantly prevented hepatic steatosis and fibrosis in diabetic mice. These beneficial effects of olmesartan on diabetic mice were associated with the attenuation of ASK1 activation in these mice. ASK1-deficient mice and wild-type mice were compared, regarding the effects of a high-fat diet. A comparison between ASK1-deficient and wild-type mice showed that ASK1 deficiency attenuated cardiac inflammation and fibrosis, as well as vascular endothelial dysfunction and remodeling induced by obesity/diabetes. The amelioration of vascular endothelial impairment by ASK1 deficiency was attributed to the prevention of endothelial NO synthase dimer disruption. ASK1 deficiency also significantly lessened hepatic steatosis in diabetic mice. In conclusion, our work provided the evidence that ASK1 is significantly activated in diet-induced diabetic mice and contributes to Cardiovascular diseases and hepatic steatosis in diabetic mice. Moreover, the beneficial effects of angiotensin II inhibition on dietary diabetic mice seem to be mediated by the inhibition of ASK1 activation.
Aristoteles Comte Alencar-filho - One of the best experts on this subject based on the ideXlab platform.
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Cardiovascular changes in patients with non-severe Plasmodium vivax malaria ☆
IJC Heart & Vasculature, 2016Co-Authors: Aristoteles Comte Alencar-filho, Wuelton Marcelo Monteiro, João Marcos Bemfica Barbosa Ferreira, Jorge L. Salinas, Camila Fabbri, André M. Siqueira, Katashi Okoshi, Marcus Vinícius Guimarães Lacerda, Marina Politi OkoshiAbstract:Background Cardiovascular system involvement in patients with Plasmodium vivax malaria has been poorly addressed. The aim of this study was to evaluate cardiac structures and function, and serum markers of Cardiovascular Injury in patients with the non-severe form of vivax malaria in Manaus, Amazonas State, Brazil.
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Cardiovascular changes in patients with non-severe Plasmodium vivax malaria
IJC Heart & Vasculature, 2016Co-Authors: Aristoteles Comte Alencar-filho, Wuelton Marcelo Monteiro, João Marcos Bemfica Barbosa Ferreira, Jorge L. Salinas, Camila Fabbri, Katashi Okoshi, Marcus Vinícius Guimarães Lacerda, André Siqueira, Marina Politi OkoshiAbstract:Background Cardiovascular system involvement in patients with Plasmodium vivax malaria has been poorly addressed. The aim of this study was to evaluate cardiac structures and function, and serum markers of Cardiovascular Injury in patients with the non-severe form of vivax malaria in Manaus, Amazonas State, Brazil.
Shokei Kim-mitsuyama - One of the best experts on this subject based on the ideXlab platform.
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LCZ696, Angiotensin II Receptor-Neprilysin Inhibitor, Ameliorates High-Salt-Induced Hypertension and Cardiovascular Injury More Than Valsartan Alone.
American Journal of Hypertension, 2015Co-Authors: Hiroaki Kusaka, Bowen Lin, Nobutaka Koibuchi, Yu Hasegawa, Daisuke Sueta, Takashi Nakagawa, Hisao Ogawa, Shokei Kim-mitsuyamaAbstract:Background LCZ696, an angiotensin receptor-neprilysin inhibitor, has recently been demonstrated to exert more beneficial effects on hypertensive or heart failure patients than conventional renin-angiotensin system blockers. However, the mechanism underlying the benefit of LCZ696 remains to be understood. The present study was undertaken to examine the effect of LCZ696 compared with valsartan on hypertension and Cardiovascular Injury. Methods (i) Using telemetry, we compared the hypotensive effect of LCZ696 and valsartan in spontaneously hypertensive rats (SHR) that were fed a high-salt diet followed by a low-salt diet. (ii) We also examined the comparative effect of LCZ696 and valsartan on salt loaded SHRcp, a model of metabolic syndrome. Results (i) LCZ696 exerted a greater blood pressure (BP) lowering effect than valsartan in SHR regardless of high-salt or low-salt intake. Additive BP reduction by LCZ696 was associated with a significant increase in urinary sodium excretion and sympathetic activity suppression. (ii) LCZ696 significantly ameliorated cardiac hypertrophy and inflammation, coronary arterial remodeling, and vascular endothelial dysfunction in high-salt loaded SHRcp compared with valsartan. Conclusions LCZ696 caused greater BP reduction than valsartan in SHR regardless of the degree of salt intake, which was associated with a significant enhancement in urinary sodium excretion and sympathetic activity suppression. Furthermore, an additive BP lowering effect of LCZ696 led to greater Cardiovascular protection in hypertensive rats.
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Eplerenone potentiates protective effects of amlodipine against Cardiovascular Injury in salt-sensitive hypertensive rats.
Hypertension Research, 2011Co-Authors: Taishi Nakamura, Eiichiro Yamamoto, Keiichiro Kataoka, Yoshiko Tokutomi, Yi Fei Dong, Hisao Ogawa, Masaya Fukuda, Hisato Nako, Osamu Yasuda, Shokei Kim-mitsuyamaAbstract:The clinical value of the combination of amlodipine and eplerenone is unclear. This study was undertaken to test whether eplerenone potentiates the protective effects of amlodipine against hypertensive Cardiovascular Injury. Salt-loaded Dahl salt-sensitive hypertensive rats (DS rats) were given (1) vehicle, (2) an antihypertensive dose of amlodipine, (3) a non-antihypertensive dose of eplerenone or (4) combined amlodipine and eplerenone for 6 weeks, and the effects on Cardiovascular injuries were compared. There was no significant difference among the four groups regarding plasma aldosterone, urine volume or urinary electrolytes. A subpressor dose of eplerenone markedly ameliorated vascular endothelial dysfunction, cardiac inflammation and fibrosis in DS rats to a similar degree as an antihypertensive dose of amlodipine. Addition of eplerenone to amlodipine, without affecting blood pressure, enhanced the improvement by amlodipine of vascular endothelial function, cardiac inflammation, fibrosis and diastolic dysfunction in DS rats. Additive beneficial effects of eplerenone were attributed to additive potentiation of eNOS and Akt phosphorylation and additive reduction of oxidative stress. Eplerenone significantly attenuated Cardiovascular NADPH oxidase activity by reducing gp91phox upregulation and attenuated the upregulation of Cardiovascular AT1 receptor, but amlodipine failed to affect them. Thus, the normalization by eplerenone of gp91phox and AT1 receptor upregulation seems to be at least partially responsible for the additive benefits of eplerenone in the prevention of hypertensive Cardiovascular Injury. The combination of amlodipine and eplerenone may be a promising therapeutic strategy for Cardiovascular disease in salt-sensitive hypertension.
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Apoptosis signal-regulating kinase 1 deficiency eliminates Cardiovascular injuries induced by high-salt diet.
Journal of Hypertension, 2011Co-Authors: Keiichiro Kataoka, Taishi Nakamura, Eiichiro Yamamoto, Yoshiko Tokutomi, Yi Fei Dong, Hisao Ogawa, Masaya Fukuda, Hidenori Ichijo, Shokei Kim-mitsuyamaAbstract:Objectives High-salt diet is closely associated with the increase in Cardiovascular events. However, the mechanism of high-salt-induced Cardiovascular Injury is unknown. The present study was undertaken to test our hypothesis that apoptosis signal-regulating kinase (ASK) 1 may be involved in salt-induced Cardiovascular Injury. Methods Wild-type and ASK1−/− mice were fed a low-salt or a high-salt diet for 10 weeks and the effects of high-salt diet on food intake, urinary volume and electrolyte excretion, and Cardiovascular Injury were compared between both groups of mice. Results High-salt diet in wild-type and ASK1−/− mice similarly increased food intake, water intake, urine volume, and urinary sodium excretion, and comparably decreased plasma renin activity and aldosterone. Thus, ASK1 appears to play a minor role in the increase in natriuresis and the decrease in plasma renin, and aldosterone caused by high-salt diet. High-salt diet enhanced the phosphorylation of Cardiovascular ASK1 in wild-type mice. High-salt diet in wild-type mice enhanced cardiac transforming growth factor-β1, interstitial fibrosis, coronary perivascular fibrosis, and inflammatory cell infiltration, and these changes were associated with the increase in cardiac superoxide and Nox2. ASK1 deficiency abolished the above-mentioned high-salt-induced cardiac Injury. High-salt diet also caused the impairment of vascular endothelium-dependent relaxation by acetylcholine and increased vascular superoxide, and Nox2 in wild-type mice, whereas it did not cause vascular Injury in ASK1−/− mice. Conclusion ASK1 is implicated in cardiac inflammation and fibrosis, and vascular endothelial dysfunction caused by high-salt diet, through the enhancement of oxidative stress.
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Ezetimibe Ameliorates Cardiovascular Complications and Hepatic Steatosis in Obese and Type 2 Diabetic db/db Mice
Journal of Pharmacology and Experimental Therapeutics, 2010Co-Authors: Masaya Fukuda, Taishi Nakamura, Keiichiro Kataoka, Yoshiko Tokutomi, Yi Fei Dong, Hisao Ogawa, Hisato Nako, Osamu Yasuda, Shokei Kim-mitsuyamaAbstract:Type 2 diabetes plays a major role in the development of Cardiovascular diseases. The present study was undertaken to investigate the effect of ezetimibe, a potent cholesterol absorption inhibitor, on Cardiovascular Injury of obese and type 2 diabetic db/db mice. Diabetic db/db mice fed western diet were given ezetimibe for 9 weeks and the effects on Cardiovascular Injury and hepatic steatosis were examined. Ezetimibe treatment of db/db mice significantly improved vascular endothelial function, which was associated with the restoration of the decreased phospho-Akt and phospho-eNOS. Moreover, ezetimibe also reduced vascular superoxide levels in db/db mice, accompanied by the attenuation of NADPH oxidase subunit gp91phox and Nox4, and the prevention of downregulation of Cu/Zn-SOD and EC-SOD. Thus, the improvement of vascular endothelial function by ezetimibe in diabetic mice seems to be attributed to the improvement of eNOS function and the attenuation of oxidative stress. Ezetimibe treatment also significantly attenuated cardiac interstitial fibrosis and coronary arterial thickening of diabetic mice and ameliorated cardiac macrophage infiltration. This improvement of cardiac Injury was also related to the attenuation of NADPH oxidase-mediated oxidative stress. Furthermore, ezetimibe significantly prevented hepatic steatosis, inflammation, and oxidative stress in diabetic mice. Our work provided the first evidence that ezetimibe prevented Cardiovascular Injury and hepatic steatosis in diabetic mice and these beneficial effects were attributed to the attenuation of oxidative stress and inflammation and the improvement of eNOS function. Therefore, we propose that ezetimibe may be a promising therapeutic drug for obese and type 2 diabetes.
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Beneficial Effects of Pioglitazone on Hypertensive Cardiovascular Injury Are Enhanced by Combination With Candesartan
Hypertension, 2008Co-Authors: Taishi Nakamura, Eiichiro Yamamoto, Keiichiro Kataoka, Takuro Yamashita, Yoshiko Tokutomi, Yi Fei Dong, Shinji Matsuba, Hisao Ogawa, Shokei Kim-mitsuyamaAbstract:The effect of pioglitazone, a peroxisome proliferator-activated receptor γ agonist, on hypertensive Cardiovascular Injury is unknown. We examined the effect of pioglitazone on hypertensive Cardiovascular Injury and the significance of combination of pioglitazone with angiotensin type 1 receptor blocker. Stroke-prone spontaneously hypertensive rats (SHRSP) were orally given pioglitazone, candesartan, or combined pioglitazone and candesartan for 4 weeks to compare their effects on cardiovasucular Injury. Pioglitazone, without lowering blood pressure, significantly suppressed cardiac inflammation and fibrosis and reduced vascular endothelial dysfunction, and these beneficial effects were associated with the reduction of superoxide by inhibition of Cardiovascular NADPH oxidase. Thus, pioglitazone protects against hypertensive Cardiovascular Injury, by inhibiting reactive oxygen species (ROS). Combination of pioglitazone and candesartan suppressed cardiac hypertrophy, inflammation, and interstitial fibrosis of SHRSP to a greater extent than either monotherapy, and reduced vascular endothelial dysfunction of SHRSP more than either monotherapy. Furthermore, more beneficial effects of their combination on Cardiovascular Injury were associated with more reduction of NADPH oxidase–mediated Cardiovascular ROS. To elucidate the underlying molecular mechanism, we examined Cardiovascular NADPH oxidase subunits. Pioglitazone monotherapy significantly attenuated Cardiovascular p22 phox and Rac1 in SHRSP, whereas pioglitazone combined with candesartan more attenuated p22 phox and significantly reduced Nox1. Thus, additive suppression of Cardiovascular NADPH oxidase by the combination was attributed to its additive attenuation of p22 phox and Nox1 protein levels. In conclusion, we showed that pioglitazone protected against hypertensive Cardiovascular damage, and the combination of pioglitazone and candesartan exerted more beneficial effects on hypertensive Cardiovascular Injury by more suppressing ROS.