Angiotensin II and Aldosterone stimulating NF-κB and AP-1 activation in hepatic fibrosis of rat

Xu, Li; Meng, Ying; Wu, Peng; Zhang, Zhen-Shu; Yang, Xi-shan

doi:10.1016/j.regpep.2006.07.011

Cited by 55 publications

(60 citation statements)

References 25 publications

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“…1,13,25,26 Our results indicate that the basal NF-B mRNA expressions in sham-operated and SD controls were comparable, whereas the levels in DOCA-salt-hypertensive rats were elevated by 3.2-fold (Figure 3A). Interestingly, hemin therapy reduced NF-B by 87.1%, whereas CrMP enhanced it.…”

Section: Effect Of Hemin On Oxidative/inflammatory Mediators Nf-b (P6mentioning

confidence: 64%

“…1,2 In mineralocorticoid-induced hypertension, the activation of JNK, TGF-␤ (TGF-␤ 1 ) and NF-B constitutes a potent prohypertrophic/remodeling axis. [2][3][4][5] The pathophysiological role of aldosterone in cardiac damage is evident in deoxycorticosterone acetate-salt (DOCA-salt) hypertension, 6 where elevated superoxide quenches NO to form peroxynitrite and 8-isoprostane, with subsequent stimulation of endothelin-1 to potentiate oxidative injury.…”

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confidence: 99%

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Interaction Among Heme Oxygenase, Nuclear Factor-κB, and Transcription Activating Factors in Cardiac Hypertrophy in Hypertension

2008

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Abstract-Deoxycorticosterone acetate-induced hypertension is a volume overload and human primary aldosteronism model characterized by severe cardiac lesions attributed to elevated inflammation, oxidative stress, fibrosis, and hypertrophy. An important cytoprotective pathway that counteracts tissue insults is the heme oxygenase (HO) system. Although the HO-1 gene promoter contains consensus binding sites for proinflammatory/oxidative transcription factors like nuclear factor-B, activating protein (AP)-1, and AP-2, the effects of HO inducers on these transcription factors in cardiac lesions of deoxycorticosterone acetate hypertension are not fully understood. Hemin therapy normalized systolic blood pressure and markedly reduced the left:right ventricular ratio, left ventricular wall thickness, and left ventricle:body weight ratio, whereas the HO blocker, chromium mesoporphyrin, exacerbated cardiac fibrosis/hypertrophy in deoxycorticosterone acetate-hypertensive rats. The cardioprotection by hemin was accompanied by increased HO-1, HO activity, cGMP, superoxide dismutase, catalase, the total antioxidant capacity alongside the reduction of 8-isoprostane, AP-1, AP-2, nuclear factor-B, and c-Jun-NH 2 -terminal kinase, whereas chromium mesoporphyrin abolished the hemin effects. Furthermore, hemin therapy attenuated transforming growth factor-␤ 1 and extracellular matrix proteins like fibronectin and collagen, with a corresponding reduction of histopathologic lesions, including longitudinal/cross-sectional muscle fiber thickness, scarring, muscular hypertrophy, coronary arteriolar thickening, and collagen deposition. The suppression of AP-1, AP-2, nuclear factor-B, and c-Jun-NH 2 -terminal kinase proinflammatory/oxidative mediators in the left ventricle of hemin-treated animals is a novel observation that may account for cardioprotection in deoxycorticosterone acetate hypertension. By concomitantly upregulating HO activity and cGMP and potentiating the total antioxidant status, hemin therapy reduced hypertension, suppressed oxidative stress, and attenuated extracellular matrix and remodeling proteins, with a reduction of histopathologic lesions that characterize cardiac fibrosis, hypertrophy, and end-stage organ damage. (Hypertension. 2008;52:910-917.)Key Words: deoxycorticosterone acetate hypertension Ⅲ heme oxygenase-1 Ⅲ hemin Ⅲ cardiac hypertrophy Ⅲ activating protein-1 Ⅲ nuclear factor B Ⅲ TGF-␤ A ldosterone induces inflammation, oxidative stress, and fibrosis by stimulating nuclear factor-B (NF-B), activating protein (AP), and c-Jun-NH2-terminal kinase (JNK). 1,2 In mineralocorticoid-induced hypertension, the activation of JNK, TGF-␤ (TGF-␤ 1 ) and NF-B constitutes a potent prohypertrophic/remodeling axis. [2][3][4][5] The pathophysiological role of aldosterone in cardiac damage is evident in deoxycorticosterone acetate-salt (DOCA-salt) hypertension, 6 where elevated superoxide quenches NO to form peroxynitrite and 8-isoprostane, with subsequent stimulation of endothelin-1 to potentiate oxidative injury. 7,8 Moreov...

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Section: Effect Of Hemin On Oxidative/inflammatory Mediators Nf-b (P6mentioning

confidence: 64%

mentioning

confidence: 99%

Interaction Among Heme Oxygenase, Nuclear Factor-κB, and Transcription Activating Factors in Cardiac Hypertrophy in Hypertension

2008

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“…Heterodimerization of c-Fos with c-Jun results in a more stable AP-1 complex that increases the capacity of c-Jun to transactivate target genes. 2 Li et al 3 demonstrated that stimulation of the AP-1 and NF-kB pathways mediates hepatic fibrogenesis induced by intrahepatic RAAS. Thus, the AP-1 (c-Fos/c-Jun heterodimers) and NF-kB pathways may participate in the process of fibrosis.…”

Section: Introductionmentioning

confidence: 99%

Rosiglitazone attenuates myocardial remodeling in spontaneously hypertensive rats

Hao

et al. 2011

Hypertens Res

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Rosiglitazone, an important peroxisome proliferator-activated receptor-c (PPAR-c) agonist, improves left ventricular (LV) hypertrophy in diet-induced hypercholesterolemic rats. However, the effects and underlying mechanisms of rosiglitazone on myocardial remodeling in spontaneous hypertension rats (SHRs) are unclear. Twenty male 8-week-old SHRs were randomly divided into two groups: one treated with oral saline (n¼10) and the other treated with rosiglitazone (5 mg kg À1 day À1 , n¼10). Ten age-matched Wistar-Kyoto rats were selected as a normal control group. Echocardiography, immunohistochemistry, real-time reverse transcriptase-PCR and western blot analysis were performed to assess the effects of rosiglitazone. After 16 weeks of treatment, LV hypertrophy was significantly attenuated by rosiglitazone (LV weight/body weight, 2.35±0.11 vs. 2.56 ± 0.14 mg g À1 ). According to the echocardiography results, thickening of the LV wall was reduced, and mid-wall fractional shortening was improved by rosiglitazone. Similarly, the excessive collagen deposition and upregulation of collagen I and collagen III seen in SHRs receiving saline were significantly attenuated in SHRs receiving rosiglitazone. In addition, rosiglitazone treatment increased the activity of matrix metalloproteinase-9 (MMP-9) and normalized the MMP-9/tissue inhibitor of metalloproteinase-1 ratio. Furthermore, activator protein-1 (AP-1) activation and nuclear factor-kappa B (NF-jB) expression were suppressed in the rosiglitazone-treated group. These results demonstrate that the PPAR-c agonist rosiglitazone had beneficial effects on myocardial remodeling in SHRs by way of decreasing AP-1 activation and NF-jB expression, which may help in further inhibiting transcription of the downstream genes involved in the pathogenesis of myocardial remodeling induced by hypertension.

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“…In contrast, antioxidant factors such as glutathione, as well as the activity of GSH peroxidase and catalase, have been reported to be low in the liver of BDL rats (28). Furthermore, it has been reported that aldosterone accelerated oxidative stress in cell culture (29). Therefore, the antifibrotic effects of eplerenone appear to be due to the suppression of oxidative stress and lipid peroxidation.…”

Section: Discussionmentioning

confidence: 97%

The effects of the selective mineralocorticoid receptor antagonist eplerenone on hepatic fibrosis induced by bile duct ligation in rat

Matono

Koda²,

Tokunaga³

et al. 2010

Int J Mol Med

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Abstract. The aim of this study was to examine the effects of eplerenone on hepatic fibrosis induced by bile duct ligation (BDL) in rat. Low-(1.0 mg/kg body weight, BW) and high-(4.0 mg/kg BW) dose eplerenone was administered orally for 21 days immediately following BDL. Fibrosis was assessed by measuring the fibrotic area after Sirius red staining. Immunostaining for ·-smooth muscle actin (SMA), 4-hydroxy-2-nonenal (4-HNE) and 8-hydroxy-2-deoxyguanosine (8-OHdG) was also carried out. Gene expression levels of procollagen-I, transforming growth factor-ß1 (TGF-ß1), connective tissue growth factor (CTGF), tissue inhibitor of metalloproteinases-1 (TIMP-1) and matrix metalloproteinase-13 (MMP-13) in the liver were examined by real-time reverse transcriptase polymerase chain reaction. Plasma angiotensin II (ATII) concentration was measured via radioimmunoassay. The area of hepatic fibrosis and ·-SMA positivity in the high-dose group was significantly decreased compared with that in the BDL group, but not in the low-dose group. 8-OHdG-positive cells in the low-and high-dose groups were significantly decreased compared with those in the BDL group. Immunostaining of 4-HNE in the high-dose group was significantly lower compared with that in the BDL group. Furthermore, TIMP-1 mRNA levels in the low-and high-dose groups were lower than that in the BDL group. The expression of TGF-ß1, CTGF, procollagen-1 and MMP-13 showed no differences. Plasma ATII concentration in the high-dose group was significantly decreased. Eplerenone attenuated the development of BDL-induced hepatic fibrosis by reducing oxidative stress, suppressing activated hepatic stellate cells and decreasing plasma ATII levels. Eplerenone may prove useful as an alternative treatment for antifibrosis therapy. IntroductionAngiotensin II (ATII) and aldosterone are the main effector peptides of the renin-angiotensin-aldosterone system (RAAS) and are known to be important mediators of hepatic fibrosis and portal hypertension (1-5). ATII and aldosterone stimulate the proliferation of hepatic stellate cells (HSC) and collagen synthesis, and are involved in the generation of reactive oxygen species (ROS) both in vitro and in vivo (6-8). ATII type 1 receptor blockers (ARB) and angiotensin-converting enzyme inhibitors (ACEI) have been reported to prevent the development of hepatic fibrosis in numerous animal (6-12) and human (13-15) studies. However, only a few studies examining the antifibrotic effects of aldosterone blockers have been reported to date. The results arising from these studies have proven to be controversial (1,2,5). Fujisawa et al (5) reported that spironolactone prevented pig serum-induced hepatic fibrosis in rats, while Oberti et al (2) showed that spironolactone did not produce any anti-fibrotic effects during bile duct ligation (BDL)-induced hepatic fibrosis.The novel aldosterone blocker eplerenone has been shown to exhibit a high specificity for mineralocorticoid receptors (16,17). While the efficacy and safety of eplerenone in the treatment of hype...

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Angiotensin II and Aldosterone stimulating NF-κB and AP-1 activation in hepatic fibrosis of rat

Cited by 55 publications

References 25 publications

Interaction Among Heme Oxygenase, Nuclear Factor-κB, and Transcription Activating Factors in Cardiac Hypertrophy in Hypertension

Interaction Among Heme Oxygenase, Nuclear Factor-κB, and Transcription Activating Factors in Cardiac Hypertrophy in Hypertension

Rosiglitazone attenuates myocardial remodeling in spontaneously hypertensive rats

The effects of the selective mineralocorticoid receptor antagonist eplerenone on hepatic fibrosis induced by bile duct ligation in rat

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