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A novel role for SIRT-1 in L-arginine protection against STZ induced myocardial fibrosis in rats.

Rizk SM, El-Maraghy SA, Nassar NN - PLoS ONE (2014)

Bottom Line: The former finding was paralleled by L-ARG induced reduction in myocardial fibrotic area compared to STZ animals evidenced histopathologically.The reduction in the fibrotic area was accompanied by a decline in fibrotic markers as evident by a decrease in expression of collagen-1 along with reductions in myocardial TGF-β, fibronectin, CTGF and BNP expression together with a decrease in TGF-β and hydroxyproline contents.However, co-administration of L-ARG and Stnl diminished the protective effect of L-ARG against STZ induced myocardial fibrosis.

View Article: PubMed Central - PubMed

Affiliation: Department of Biochemistry, Faculty of Pharmacy, Cairo University, Cairo, Egypt.

ABSTRACT

Background: L-arginine (L-ARG) effectively protects against diabetic impediments. In addition, silent information regulator (SIRT-1) activators are emerging as a new clinical concept in treating diabetic complications. Accordingly, this study aimed at delineating a role for SIRT-1 in mediating L-ARG protection against streptozotocin (STZ) induced myocardial fibrosis.

Methods: Male Wistar rats were allocated into five groups; (i) normal control rats received 0.1 M sodium citrate buffer (pH 4.5); (ii) STZ at the dose of 60 mg/kg dissolved in 0.1 M sodium citrate buffer (pH 4.5); (iii) STZ + sirtinol (Stnl; specific inhibitor of SIRT-1; 2 mg/Kg, i.p.); (iv) STZ + L-ARG given in drinking water (2.25%) or (v) STZ + L-ARG + Stnl.

Results: L-ARG increased myocardial SIRT-1 expression as well as its protein content. The former finding was paralleled by L-ARG induced reduction in myocardial fibrotic area compared to STZ animals evidenced histopathologically. The reduction in the fibrotic area was accompanied by a decline in fibrotic markers as evident by a decrease in expression of collagen-1 along with reductions in myocardial TGF-β, fibronectin, CTGF and BNP expression together with a decrease in TGF-β and hydroxyproline contents. Moreover, L-ARG increased MMP-2 expression in addition to its protein content while decreasing expression of PAI-1. Finally, L-ARG protected against myocardial cellular death by reduction in NFκ-B mRNA as well as TNF-α level in association with decline in Casp-3 and FAS expressions andCasp-3protein content in addition to reduction of FAS positive cells. However, co-administration of L-ARG and Stnl diminished the protective effect of L-ARG against STZ induced myocardial fibrosis.

Conclusion: Collectively, these findings associate a role for SIRT-1 in L-ARG defense against diabetic cardiac fibrosis via equilibrating the balance between profibrotic and antifibrotic mediators.

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Related in: MedlinePlus

Effect of STZ alone or in combination with L-ARG or L-ARG + Stnl on caspase-3 (Casp-3) mRNA expression (A) and activity (B) as well as (C) FAS mRNA expression and (D) % FAS positive cells.Data represent the means of six experiments ±SEM; *, #, ω and δ P<0.05 compared with CONT, STZ, STZ + Stnl and STZ + Stnl + L-ARG, respectively, using one-way ANOVA followed by Tukey's Multiple Comparison Test.
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pone-0114560-g005: Effect of STZ alone or in combination with L-ARG or L-ARG + Stnl on caspase-3 (Casp-3) mRNA expression (A) and activity (B) as well as (C) FAS mRNA expression and (D) % FAS positive cells.Data represent the means of six experiments ±SEM; *, #, ω and δ P<0.05 compared with CONT, STZ, STZ + Stnl and STZ + Stnl + L-ARG, respectively, using one-way ANOVA followed by Tukey's Multiple Comparison Test.

Mentions: STZ diabetic rats produced significant apoptosis in left ventricular myocardial tissue as manifested by increased Casp- 3 and FAS mRNA by 3.3 and 2.5 folds, respectively compared to their respective controls, with no significant difference with STZ + Stnl or STZ + Stnl + L-ARG groups. By the same token, Casp-3 activity as well as the number of FAS positive cells were increased in STZ animals reaching to 249% 821% as compared to normal ones, respectively. On the other hand, L-ARG administered concomitantly with STZ normalized Casp-3 expression and activity as well as FAS expression. L-ARG significantly reduced the number of FAS positive cells as compared to STZ animals (Fig. 5).


A novel role for SIRT-1 in L-arginine protection against STZ induced myocardial fibrosis in rats.

Rizk SM, El-Maraghy SA, Nassar NN - PLoS ONE (2014)

Effect of STZ alone or in combination with L-ARG or L-ARG + Stnl on caspase-3 (Casp-3) mRNA expression (A) and activity (B) as well as (C) FAS mRNA expression and (D) % FAS positive cells.Data represent the means of six experiments ±SEM; *, #, ω and δ P<0.05 compared with CONT, STZ, STZ + Stnl and STZ + Stnl + L-ARG, respectively, using one-way ANOVA followed by Tukey's Multiple Comparison Test.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4264750&req=5

pone-0114560-g005: Effect of STZ alone or in combination with L-ARG or L-ARG + Stnl on caspase-3 (Casp-3) mRNA expression (A) and activity (B) as well as (C) FAS mRNA expression and (D) % FAS positive cells.Data represent the means of six experiments ±SEM; *, #, ω and δ P<0.05 compared with CONT, STZ, STZ + Stnl and STZ + Stnl + L-ARG, respectively, using one-way ANOVA followed by Tukey's Multiple Comparison Test.
Mentions: STZ diabetic rats produced significant apoptosis in left ventricular myocardial tissue as manifested by increased Casp- 3 and FAS mRNA by 3.3 and 2.5 folds, respectively compared to their respective controls, with no significant difference with STZ + Stnl or STZ + Stnl + L-ARG groups. By the same token, Casp-3 activity as well as the number of FAS positive cells were increased in STZ animals reaching to 249% 821% as compared to normal ones, respectively. On the other hand, L-ARG administered concomitantly with STZ normalized Casp-3 expression and activity as well as FAS expression. L-ARG significantly reduced the number of FAS positive cells as compared to STZ animals (Fig. 5).

Bottom Line: The former finding was paralleled by L-ARG induced reduction in myocardial fibrotic area compared to STZ animals evidenced histopathologically.The reduction in the fibrotic area was accompanied by a decline in fibrotic markers as evident by a decrease in expression of collagen-1 along with reductions in myocardial TGF-β, fibronectin, CTGF and BNP expression together with a decrease in TGF-β and hydroxyproline contents.However, co-administration of L-ARG and Stnl diminished the protective effect of L-ARG against STZ induced myocardial fibrosis.

View Article: PubMed Central - PubMed

Affiliation: Department of Biochemistry, Faculty of Pharmacy, Cairo University, Cairo, Egypt.

ABSTRACT

Background: L-arginine (L-ARG) effectively protects against diabetic impediments. In addition, silent information regulator (SIRT-1) activators are emerging as a new clinical concept in treating diabetic complications. Accordingly, this study aimed at delineating a role for SIRT-1 in mediating L-ARG protection against streptozotocin (STZ) induced myocardial fibrosis.

Methods: Male Wistar rats were allocated into five groups; (i) normal control rats received 0.1 M sodium citrate buffer (pH 4.5); (ii) STZ at the dose of 60 mg/kg dissolved in 0.1 M sodium citrate buffer (pH 4.5); (iii) STZ + sirtinol (Stnl; specific inhibitor of SIRT-1; 2 mg/Kg, i.p.); (iv) STZ + L-ARG given in drinking water (2.25%) or (v) STZ + L-ARG + Stnl.

Results: L-ARG increased myocardial SIRT-1 expression as well as its protein content. The former finding was paralleled by L-ARG induced reduction in myocardial fibrotic area compared to STZ animals evidenced histopathologically. The reduction in the fibrotic area was accompanied by a decline in fibrotic markers as evident by a decrease in expression of collagen-1 along with reductions in myocardial TGF-β, fibronectin, CTGF and BNP expression together with a decrease in TGF-β and hydroxyproline contents. Moreover, L-ARG increased MMP-2 expression in addition to its protein content while decreasing expression of PAI-1. Finally, L-ARG protected against myocardial cellular death by reduction in NFκ-B mRNA as well as TNF-α level in association with decline in Casp-3 and FAS expressions andCasp-3protein content in addition to reduction of FAS positive cells. However, co-administration of L-ARG and Stnl diminished the protective effect of L-ARG against STZ induced myocardial fibrosis.

Conclusion: Collectively, these findings associate a role for SIRT-1 in L-ARG defense against diabetic cardiac fibrosis via equilibrating the balance between profibrotic and antifibrotic mediators.

Show MeSH
Related in: MedlinePlus