Angiotensin II Receptor Blocker Reduces Oxidative Stress and Attenuates Hypoxia-Induced Left Ventricular Remodeling in Apolipoprotein E-Knockout Mice

Yamashita, Chika; Hayashi, Toshio; Mori, Tatsuhiko; Tazawa, Naoko; Kwak, Cheol; Nakano, Daisuke; Sohmiya, Koichi; Okada, Yoshinori; Kitaura, Yasushi; Matsumura, Yasuo

doi:10.1291/hypres.30.1219

Cited by 42 publications

(54 citation statements)

References 47 publications

(29 reference statements)

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“…8 We speculated that the inhibitory effects of losartan on LPS-induced proinflammatory gene expression were mediated by IkK-IkB-NFkB signaling because studies showed that AT1R blockers exerted antiinflammatory effects by suppressing IkK-IkB-NFkB activation. 15,16 However, our data show that losartan has no effect on LPS-induced IkB phosphorylation, suggesting that losartan does not inhibit LPSinduced signaling through the IkK-IkB-NFkB pathway, at least at the level of NF-kB activation.…”

Section: Discussionmentioning

confidence: 56%

Losartan inhibits LPS-induced inflammatory signaling through a PPARγ-dependent mechanism in human THP-1 macrophages

Nakajima

Kuba

et al. 2010

Hypertens Res

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Macrophages have critical roles in the pathogenesis of atherosclerosis by activating the innate immune system and producing inflammatory cytokines. Accumulating evidence indicates that angiotensin type 1 receptor (AT1R) blockers exert antiinflammatory effects in inflammatory diseases including atherosclerosis. In this study, we investigated the effect of losartan, an AT1R blocker, on the proinflammatory gene expression induced by bacterial lipopolysaccharide (LPS) in a well-defined in vitro human THP-1 macrophage system. We found that losartan significantly attenuated the LPS-induced expression of proinflammatory genes TNF-a, IL-8 and COX-2. However, exogenous angiotensin II (AngII) had no effect on LPS-induced inflammatory signaling despite the expression of AT1R. In addition, losartan did not block LPS-induced IjB phosphorylation, which is downstream of Toll-like receptor activation. Peroxisome proliferator-activated receptor-gamma (PPARc) antagonists, GW9662 and T0070907, reversed the inhibitory effects of losartan on LPS-induced TNF-a and IL-8 expression in THP-1 macrophages. These observations suggest that losartan inhibits LPS-induced proinflammatory gene expression in macrophages by activating the PPARc pathway rather than by the competitive inhibition of AT1R binding to AngII.

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Section: Discussionmentioning

confidence: 56%

Losartan inhibits LPS-induced inflammatory signaling through a PPARγ-dependent mechanism in human THP-1 macrophages

Nakajima

Kuba

et al. 2010

Hypertens Res

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“…Briefly, in nucleated transverse sections stained with hematoxylin-eosin, cardiomyocytes with both a clear nucleus and intact cellular membrane were measured using NIS-Elements version 3.07 software (Nikon), and at least 30 cardiomyocytes were analyzed per heart. After staining with Sirius red, color images were randomly selected from five high-power fields (at a magnification of ϫ200), and the collagen volume ratio (%) was calculated as described elsewhere (33). The LV free wall myocardium was fixed in 4% paraformaldehyde containing 0.25% glutaraldehyde and 4.5% sucrose.…”

Section: Animalsmentioning

confidence: 99%

Hydrogen gas attenuates embryonic gene expression and prevents left ventricular remodeling induced by intermittent hypoxia in cardiomyopathic hamsters

Kato

Nomura

Sakamoto

et al. 2014

American Journal of Physiology-Heart and Circulatory Physiology

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T. Hydrogen gas attenuates embryonic gene expression and prevents left ventricular remodeling induced by intermittent hypoxia in cardiomyopathic hamsters. Am J Physiol Heart Circ Physiol 307: H1626 -H1633, 2014. First published October 3, 2014; doi:10.1152/ajpheart.00228.2014.-The prevalence of sleep apnea is very high in patients with heart failure (HF). The aims of this study were to investigate the influence of intermittent hypoxia (IH) on the failing heart and to evaluate the antioxidant effect of hydrogen gas. Normal male Syrian hamsters (n ϭ 22) and cardiomyopathic (CM) hamsters (n ϭ 33) were exposed to IH (repeated cycles of 1.5 min of 5% oxygen and 5 min of 21% oxygen for 8 h during the daytime) or normoxia for 14 days. Hydrogen gas (3.05 vol/100 vol) was inhaled by some CM hamsters during hypoxia. IH increased the ratio of early diastolic mitral inflow velocity to mitral annulus velocity (E/e=, 21.8 vs. 16.9) but did not affect the LV ejection fraction (EF) in normal Syrian hamsters. However, IH increased E/e= (29.4 vs. 21.5) and significantly decreased the EF (37.2 vs. 47.2%) in CM hamsters. IH also increased the cardiomyocyte cross-sectional area (672 vs. 443 m 2 ) and interstitial fibrosis (29.9 vs. 9.6%), along with elevation of oxidative stress and superoxide production in the left ventricular (LV) myocardium. Furthermore, IH significantly increased the expression of brain natriuretic peptide, ␤-myosin heavy chain, c-fos, and c-jun mRNA in CM hamsters. Hydrogen gas inhalation significantly decreased both oxidative stress and embryonic gene expression, thus preserving cardiac function in CM hamsters. In conclusion, IH accelerated LV remodeling in CM hamsters, at least partly by increasing oxidative stress in the failing heart. These findings might explain the poor prognosis of patients with HF and sleep apnea. heart failure; intermittent hypoxia; oxidative stress; cardiomyopathic hamster; hydrogen gas SLEEP APNEA SYNDROME (SAS) is a breathing disorder characterized by recurrent episodes of apnea and/or hypopnea that increases the risk of cardiovascular morbidity and mortality (10,19,26). In persons with SAS, recurrent hypopnea/apnea leads to intermittent hypoxia (IH). The prevalence of SAS is much higher in patients with established cardiovascular disease, and central sleep apnea is associated with the more severe forms of heart failure (17), although the mechanisms underlying periodic breathing in patients with heart failure (HF) are complex and multifactorial.Oxidative stress arises because of an imbalance between free radical production and endogenous antioxidant defenses and is increased in patients with HF (4). Free radicals have also been linked to endothelial dysfunction and increased sympathetic tone (2, 16), whereas intravenous infusion of antioxidants reduces free radical levels and attenuates sympathetic activity in animal models of HF (32). It has been suggested that hydrogen gas produced in the large intestine by intestinal bacteria might scavenge hydroxyl radicals (6), and it was recen...

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“…Inhibiting both angiotensin II type 1 and type 2 receptors with Sar1-Ile8-Ang II reduces collagen type I and elastin deposition but also increases vascular stiffness, fibronectin, and MMP-2 activity [115]. Olmesartan improves LV remodeling in apo E null mice by inhibiting nuclear factor -B (NF-B) and MMP-9 activities [116]. Yang and colleagues reported that valsartan decreased levels of MMP-2, -3, and -9 post-MI [117].…”

Section: Ace Inhibitors and Angiotensin II Receptor Inhibitors-angiotmentioning

confidence: 99%

Matrix Metalloproteinases: Drug Targets for Myocardial Infarction

Yabluchanskiy¹,

Li²,

Chilton³

et al. 2013

CDT

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Myocardial infarction (MI) remains a major cause of morbidity and mortality worldwide. Rapid advances in the treatment of acute MI have significantly improved short-term outcomes in patient, due in large part to successes in preventing myocardial cell death and limiting infarct area during the time of ischemia and subsequent reperfusion. Matrix metalloproteases (MMPs) play key roles in post-MI cardiac remodeling and in the development of adverse outcomes. This review highlights the importance of MMPs in the injury and remodeling response of the left ventricle and also discusses their potential as therapeutic targets Additional pre-clinical and clinical research is needed to further investigate and understand the cardioprotective effects of MMPs inhibitors.

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Angiotensin II Receptor Blocker Reduces Oxidative Stress and Attenuates Hypoxia-Induced Left Ventricular Remodeling in Apolipoprotein E-Knockout Mice

Cited by 42 publications

References 47 publications

Losartan inhibits LPS-induced inflammatory signaling through a PPARγ-dependent mechanism in human THP-1 macrophages

Losartan inhibits LPS-induced inflammatory signaling through a PPARγ-dependent mechanism in human THP-1 macrophages

Hydrogen gas attenuates embryonic gene expression and prevents left ventricular remodeling induced by intermittent hypoxia in cardiomyopathic hamsters

Matrix Metalloproteinases: Drug Targets for Myocardial Infarction

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