title: A novel role for SIRT-1 in L-arginine protection against STZ induced myocardial fibrosis in rats.
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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Biochemistry, Faculty of Pharmacy, Cairo University, Cairo, Egypt.
authors.forename: Sherine M
authors.initials: SM
authors.lastname: Rizk
authors.affiliation: Department of Biochemistry, Faculty of Pharmacy, Cairo University, Cairo, Egypt.
authors.forename: Shohda A
authors.initials: SA
authors.lastname: El-Maraghy
authors.affiliation: Department of Pharmacology and Toxicology, Faculty of Pharmacy, Cairo University, Cairo, Egypt.
authors.forename: Noha N
authors.initials: NN
authors.lastname: Nassar
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001120:Arginine / Q000494:pharmacology*; D001549:Benzamides / Q000494:pharmacology; D015415:Biomarkers / Q000378:metabolism; D001786:Blood Glucose / Q000378:metabolism; D019610:Cytoprotection / Q000187:drug effects*; D048909:Diabetes Complications / Q000097:blood / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D005215:Fasting / Q000097:blood; D005355:Fibrosis; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D006442:Glycated Hemoglobin / Q000378:metabolism; D007328:Insulin / Q000097:blood; D053583:Interleukin-1beta / Q000378:metabolism; D008297:Male; D020778:Matrix Metalloproteinase 2 / Q000235:genetics / Q000378:metabolism; D009206:Myocardium / Q000378:metabolism / Q000473:pathology*; D009284:Naphthols / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D056564:Sirtuin 1 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D013311:Streptozocin / Q000009:adverse effects*; D016212:Transforming Growth Factor beta / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D001120:Arginine; D001549:Benzamides; D015415:Biomarkers; D001786:Blood Glucose; D006442:Glycated Hemoglobin; D007328:Insulin; D053583:Interleukin-1beta; D020778:Matrix Metalloproteinase 2; D009284:Naphthols; D056564:Sirtuin 1; D013311:Streptozocin; D016212:Transforming Growth Factor beta; D014409:Tumor Necrosis Factor-alpha; C439060:sirtinol; C488368:Sirt1 protein, rat