Angiotensin-II Receptor Blocker Exerts Cardioprotection in Diabetic Rats Exposed to Hypoxia

Inamoto, Sakiko; Hayashi, Toshio; Tazawa, Naoko; Mori, Tatsuhiko; Yamashita, Chika; Nakano, Daisuke; Matsumura, Yasuo; Okuda, Naoki; Sohmiya, Koichi; Sakai, Akiko; Furuya, Eisuke; Kitaura, Yasushi

doi:10.1253/circj.70.787

Cited by 22 publications

(31 citation statements)

References 32 publications

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“…In response to hypoxia, the heart also generates ROS, resulting in cardiac hypertrophy and expression of fetal cardiac genes (Inamoto et al 2006, Kontaraji et al 2007, Yamashita et al 2007) through various signaling cascades (Seta & Millhorn 2004). A previous study has shown that the density of binding sites for UII in sarcolemma of the myocardium increased in rats exposed to chronic hypoxia (Zhang et al 2002).…”

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confidence: 99%

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Angiotensin II and the JNK pathway mediate urotensin II expression in response to hypoxia in rat cardiomyocytes

Chiu¹,

Wang²,

Shyu³

2014

Journal of Endocrinology

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Cardiomyocyte hypoxia causes cardiac hypertrophy through cardiac-restricted gene expression. Urotensin II (UII) cooperates with activating protein 1 (AP1) to regulate cardiomyocyte growth in response to myocardial injuries. Angiotensin II (AngII) stimulates UII expression, reactive oxygen species (ROS) production, and cardiac hypertrophy. This study aimed to evaluate the expression of UII, ROS, and AngII as well as their genetic transcription after hypoxia treatment in neonatal cardiomyocytes. Cultured neonatal rat cardiomyocytes were subjected to hypoxia for different time periods. UII (Uts2) protein levels increased after 2.5% hypoxia for 4 h with earlier expression of AngII and ROS. Both hypoxia and exogenously added AngII or Dp44mT under normoxia stimulated UII expression, whereas AngII receptor blockers, JNK inhibitors (SP600125), JNK siRNA, or N-acetyl-L-cysteine (NAC) suppressed UII expression. The gel shift assay indicated that hypoxia induced an increase in DNA-protein binding between UII and AP1. The luciferase assay confirmed an increase in transcription activity of AP1 to the UII promoter under hypoxia. After hypoxia, an increase in 3 H-proline incorporation in the cardiomyocytes and expression of myosin heavy chain protein, indicative of cardiomyocyte hypertrophy, were observed. In addition, hypoxia increased collagen I expression, which was inhibited by SP600125, NAC, and UII siRNA. In summary, hypoxia in cardiomyocytes increases UII and collagen I expression through the induction of AngII, ROS, and the JNK pathway causing cardiomyocyte hypertrophy and fibrosis.

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confidence: 99%

“…Interestingly, UII-R upregulation in the myocardium of hypoxic rats was accompanied by ventricular hypertrophy (Huang et al 2006). Hypoxia can also stimulate cardiomyocytes to secrete cytokines and growth factors (Inamoto et al 2006). However, the effect of hypoxia on UII expression in cardiomyocytes is not yet fully understood.…”

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confidence: 99%

Angiotensin II and the JNK pathway mediate urotensin II expression in response to hypoxia in rat cardiomyocytes

Chiu¹,

Wang²,

Shyu³

2014

Journal of Endocrinology

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“…We have already indicated that elevated RV pressure may have little effect on the LV myocardium. 24 Therefore, the LV remodeling observed in this study might be caused by the intermittent hypoxic stress itself. However, Dematteis et al 25 showed that exposure to intermittent hypoxia for 35 days was associated with hypertensive surges during exposure to hypoxic conditions.…”

Section: Discussionmentioning

confidence: 76%

“…18,24 Furthermore, a chymase inhibitor successfully suppressed the intermittent hypoxia-induced LV remodeling. 35 The renin-angiotensin system has been reported to interact with pro-inflammatory cytokines and activate a redox-sensitive transcription factor termed nuclear factor-kB (NF-kB).…”

Section: Pitavastatin Attenuates Hypoxia-induced LV Remodeling S Inammentioning

confidence: 98%

Pitavastatin reduces oxidative stress and attenuates intermittent hypoxia-induced left ventricular remodeling in lean mice

et al. 2010

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We have reported previously that intermittent hypoxia related to sleep apnea induces cardiovascular remodeling secondary to the oxidative stress. The aim of this study was to examine the effect of pitavastatin as an antioxidant to prevent intermittent hypoxia-induced left ventricular (LV) remodeling in mice without hypercholesterolemia. Eight-week-old male C57BL/6J mice (n¼35) were exposed to intermittent hypoxia (30 s exposure to 5% oxygen, followed by 30 s exposure to 21% oxygen) for 8 h per day during the daytime or maintained under normoxic conditions; in addition, they were either treated with pitavastatin (3 mg kg À1 per day) or vehicle for 10 days. After cardiac catheterization and blood sampling, the LV myocardium was examined. The systemic blood pressure and plasma level of total cholesterol were similar among the four groups. Intermittent hypoxia significantly increased the expression levels of 4-hydroxy-2-nonenal (4-HNE) proteins, TNF-a and TGF-b mRNA, and also the number of terminal deoxynucleotidyl transferase-mediated dUTP-biotin end labeling (TUNEL)-positive myocardial cells in the LV myocardium. In addition, enhanced hypertrophy of the cardiomyocytes, perivascular fibrosis and histological degeneration were observed in the mice exposed to hypoxic stress. Treatment with pitavastatin significantly suppressed the expression levels of the 4-HNE proteins, cytokines, superoxide production and TUNEL-positive myocardial cells in the LV myocardium, consequently attenuating the hypoxia-induced histological changes. Pitavastatin preserved, at least partially, the morphological structure of the LV myocardium in lean mice exposed to intermittent hypoxia, through its antioxidant effect.

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“…1 AngII is a major regulator of blood pressure (BP), electrolyte balance and endocrine function related to cardiovascular homeostasis as well as disease. 2,3 Many AT1 receptor blockers (ARBs) are available for clinical use, but when their efficacy has been compared, differences have been observed as pleiotropic effects, such as regression of left ventricular mass, 4 a reduction in renal nitric oxide (NO) production, 5,6 lowering of plasma levels of plasminogen activator inhibitor type-1 antigen and monocyte chemoattractant protein-1, 7 and prevention of human coronary artery contraction, 8 except with regard to their ability to lower BP. Therefore, these abilities of ARBs may not be class effects.…”

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Do Valsartan and Losartan Have the Same Effects in the Treatment of Coronary Artery Disease?

Iwata

Miura

Imaizumi

et al. 2007

Circ J

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Background Many angiotensin II type 1 receptor blockers (ARBs) are available for clinical use, but because they do not all have the same effects, the present study investigated whether all benefits conferred by ARBs are class effects. Methods and Results Study 1 was a case -control study of patients with coronary artery disease, which showed that a non-depressor dose of valsartan significantly decreased the rate of target lesion revascularization at 6 months after stenting compared with the control group without ARB treatment. In Study 2, 44 patients with acute myocardial infarction who randomly received an initial lower dose of either valsartan or losartan after stenting were evaluated. The late loss and decrease in %diameter stenosis in the valsartan group were significantly lower than those in the losartan group as assessed by quantitative coronary angiography after 6 months. In addition, the valsartan group showed a significantly lower expression of intracellular adhesion molecule-1 and L-selectin. Conclusion A non-depressor dose of ARB may have beneficial effects on coronary restenosis that are associated with the regulation of adhesion molecules, and these effects might not be a class effect of ARBs. (Circ J 2007; 71: 32 -38)

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Angiotensin-II Receptor Blocker Exerts Cardioprotection in Diabetic Rats Exposed to Hypoxia

Cited by 22 publications

References 32 publications

Angiotensin II and the JNK pathway mediate urotensin II expression in response to hypoxia in rat cardiomyocytes

Angiotensin II and the JNK pathway mediate urotensin II expression in response to hypoxia in rat cardiomyocytes

Pitavastatin reduces oxidative stress and attenuates intermittent hypoxia-induced left ventricular remodeling in lean mice

Do Valsartan and Losartan Have the Same Effects in the Treatment of Coronary Artery Disease?

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