Deficiency of inducible nitric oxide synthase exacerbates hepatic fibrosis in mice fed high-fat diet

Chen, Yi; Hozawa, Shigenari; Sawamura, Sadaaki; Sato, Shinkichi; Fukuyama, Naoto; Tsuji, Chizuko; Mine, Tetsuya; Okada, Yasunori; Tanino, Ryuzaburo; Ogushi, Yoichi; Nakazawa, Hiroe

doi:10.1016/j.bbrc.2004.10.202

Cited by 41 publications

(34 citation statements)

References 34 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…It is possible that the addition of fat to the diet may alter the expression and activity of iNOS and/or other factors, which modifies physiological outcome. Moreover, in the work of Chen et al, 55 the lack of protein expression, following the ablation of the iNOS gene was not demonstrated. Thus, it is uncertain whether iNOS activity and its signaling effects were utterly abolished.…”

Section: Discussionmentioning

confidence: 93%

“…These results, together with our present findings, illustrate the positive association between MMP-9 expression and liver fibrosis in response to high-cholesterol/cholate consumption. Chen et al 55 also demonstrated an increase in MMP-9 in WT but not in their iNOS KO mice following the consumption of HFHCD. However, in their study, an increase in liver fibrosis was observed in iNOS KO mice compared with WT mice.…”

Section: Discussionmentioning

confidence: 94%

See 1 more Smart Citation

The role of iNOS in cholesterol-induced liver fibrosis

Anavi

Eisenberg-Bord

Hahn-Obercyger

et al. 2015

Laboratory Investigation

View full text Add to dashboard Cite

Accumulation of cholesterol in the liver is associated with the development of non-alcoholic steatohepatitis-related fibrosis. However, underlying mechanisms are not well understood. The present study investigated the role of inducible nitric oxide synthase (iNOS) in cholesterol-induced liver fibrosis by feeding wild-type (WT) and iNOS-deficient mice with control or high-cholesterol diet (HCD) for 6 weeks. WT mice fed with HCD developed greater liver fibrosis, compared with iNOS-deficient mice, as evident by Sirius red staining and higher expression levels of profibrotic genes. Enhanced liver fibrosis in the presence of iNOS was associated with hypoxia-inducible factor-1a stabilization, matrix metalloproteinase-9 expression, and enhanced hepatic DNA damage. The profibrotic role of iNOS was also demonstrated in vivo using a selective inhibitor of iNOS as well as in vitro in a rat liver stellate cell line (HSC-T6). In conclusion, these findings suggest that iNOS is an important mediator in HCD-induced liver fibrosis.Laboratory Investigation (2015) 95, 914-924;

show abstract

Section: Discussionmentioning

confidence: 93%

Section: Discussionmentioning

confidence: 94%

The role of iNOS in cholesterol-induced liver fibrosis

Anavi

Eisenberg-Bord

Hahn-Obercyger

et al. 2015

Laboratory Investigation

View full text Add to dashboard Cite

show abstract

“…First, the fact that general inhibition of the activity of all NOS isoforms, and hence nitric oxide production, by prolonged sustained administration of N(G)-nitro-L-arginine methyl ester to rats, leads to considerable fibrotic degeneration in organs such as the heart, liver and kidney, independent of hemodynamic factors that may contribute to this process. [21][22][23][24][25] Second, specific genetic blockade of iNOS in the iNOS knockout mice leads to exacerbation of experimental fibrosis of the kidney and liver, 26,27 and the chronic inhibition of iNOS activity in rats by N6-(1-iminoethyl)-L-lysine dihydrochloride (L-NIL) intensifies aging-related fibrosis of the arterial wall and of the experimentally induced Peyronie's disease-like fibrotic plaque in the penis. 28,29 Third, administration of iNOS cDNA in the latter model reduces the fibrotic plaque.…”

Section: Antifibrotic Role Of No Following Cavernosal Nerve Resectionmentioning

confidence: 99%

Rationale for phosphodiesterase 5 inhibitor use post-radical prostatectomy: experimental and clinical review

et al. 2007

View full text Add to dashboard Cite

Erectile dysfunction (ED) is a common complication after radical prostatectomy and results from trauma sustained by the cavernosal nerves. This is a major concern for patients and often affects treatment decisions. The likely mechanism for post-prostatectomy ED is through corporal venoocclusive dysfunction. There is an increasing amount of evidence to suggest that phosphodiesterase 5 inhibitors (PDE5 inhibitors), when given on a continuous long-term basis, can help to prevent and reverse ED after surgery. In this review article we will examine the pathophysiology of postprostatectomy ED and discuss the experimental and available clinical evidence for administering PDE5 inhibitors after prostatectomy. Erectile dysfunction is common following radical prostatectomyRecent data suggest that approximately 161 000 men per year undergo a radical prostatectomy in the United States. 1 It is thought that many more men who are diagnosed with early-stage prostate cancer would accept this surgical form of treatment for their newly diagnosed disease if it were not for the possibility of the development of erectile dysfunction (ED). This common complication after radical prostatectomy is largely due to trauma sustained by the cavernosal nerves and is still widely encountered even after the most recent advances in surgical technique to spare the nerves. [2][3][4][5] Of men that are potent before surgery, only about 40-74% of men regain sexual function. [4][5][6][7] In fact, 41.9% of men reported that their sexual performance was a moderate to large problem after surgery 7 and patients appear to value sexual function so highly that they are often willing to choose therapy that offers better potency with lower life expectancy than options that offer longer life expectancy and lower potency rates. 8 Radical prostatectomy seems to disrupt and/or damage the neurovascular mechanisms responsible for eliciting an erection thereby resulting in either temporary or permanent ED postoperatively. In its mildest form, apparent in a successful bilateral nerve sparing prostatectomy, the trauma resulting from surgical manipulation of the neurovascular bundles may result in a neuropraxia leading to temporary ED. The most severe form of ED results from a non-nerve sparing prostatectomy where both nerves are transected, either volitionally or unrecognized at the time of surgery, and this leads to the complete loss of neuroregulatory functions in the corpora cavernosa. CVOD is the most common form of ED following radical prostatectomyInjury to the cavernosal nerves results in the atrophy and degradation of the underlying cavernosal smooth muscle, which, besides resulting in ED, may also lead to a decrease in penile weight. 9 Histologically, such a neuropraxia/neurotomy leads to apoptosis of the cavernosal smooth muscle and an excessive deposition of collagen within the cavernosa, which clinically results in corporal

show abstract

“…[14][15][16][17][18][19][20][21][22][23] The expression of iNOS in certain non-immunological tissues is assumed to be a defense mechanism against fibrosis. [24][25][26][27][28][29] The nitric oxide produced by iNOS, besides inhibiting collagen synthesis and the TGFb1 pathway, also quenches reactive oxygen species, and in some cases, the differentiation of fibroblasts to myofibroblasts, the cells that produce collagen in many fibrotic conditions. [30][31][32] In a recent study, we have shown that the PDE5 inhibitor, vardenafil, given for 45 days in the drinking water to rats subjected to bilateral cavernosal nerve resection (BCNR) [33][34][35] prevented the development of CVOD and the underlying SMC loss and fibrosis in the corpora cavernosa.…”

Section: Introductionmentioning

confidence: 99%

Long-term continuous sildenafil treatment ameliorates corporal veno-occlusive dysfunction (CVOD) induced by cavernosal nerve resection in rats

et al. 2007

View full text Add to dashboard Cite

It was recently reported in the rat that vardenafil given in a continuous long-term manner was successful in preventing smooth muscle fibrosis in the penile corpora cavernosa and corporal venoocclusive dysfunction (CVOD) that occur following bilateral cavernosal nerve resection (BCNR), a model for human erectile dysfunction after radical prostatectomy. To expand on this finding and to determine whether this effect was common to other PDE5 inhibitors, and occurred in part by stimulation of the spontaneous induction of inducible nitric oxide synthase (iNOS, also known as NOS2), male Fischer 344 rats (N ¼ 10/group) were subjected to either BCNR or unilateral cavernosal nerve resection (UCNR) and treated with sildenafil (20 mg kg À1 day À1 ) in the drinking water daily for 45 days. Additional BCNR groups received L-NIL (6.7 mg kg À1 day À1 ) as inhibitor of iNOS activity, with or without concurrent sildenafil administration. It was determined that sildenafil, like vardenafil, (1) prevented the 30% decrease in the smooth muscle cell/collagen ratio, and the 3-4-fold increase in apoptosis and reduction in cell proliferation, and partially counteracted the increase in collagen, seen with both UCNR and BCNR; and (2) normalized the CVOD, measured by dynamic infusion cavernosometry, induced by both BCNR and UCNR. The long-term inhibition of iNOS activity exacerbated corporal fibrosis and CVOD in the BCNR rats, but sildenafil functional effects were not affected by L-NIL. These data suggest that the salutary effects of continuous long-term PDE5 inhibitors on erectile function post-cavernosal nerve resection involve their ability to prevent the alterations in corporal histology induced by cavernosal nerve damage, in a process apparently independent from endogenous iNOS induction.

show abstract

Deficiency of inducible nitric oxide synthase exacerbates hepatic fibrosis in mice fed high-fat diet

Cited by 41 publications

References 34 publications

The role of iNOS in cholesterol-induced liver fibrosis

The role of iNOS in cholesterol-induced liver fibrosis

Rationale for phosphodiesterase 5 inhibitor use post-radical prostatectomy: experimental and clinical review

Long-term continuous sildenafil treatment ameliorates corporal veno-occlusive dysfunction (CVOD) induced by cavernosal nerve resection in rats

Contact Info

Product

Resources

About