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

• Published in: PloS one 2014-12, Vol.9 (12), p.e114560
• Main Authors: Rizk, Sherine M, El-Maraghy, Shohda A, Nassar, Noha N
• Format: Article
• Language: English
• Subjects: Animals; Apoptosis; Apoptosis - drug effects; Arginine; Arginine - pharmacology; Benzamides - pharmacology; Biochemistry; Biology and Life Sciences; Biomarkers - metabolism; Blood Glucose - metabolism; Buffers; Cardiomyopathy; Care and treatment; Cell cycle; Cell death; Citric acid; Collagen; Complications; Connective tissue growth factor; Cytokines; Cytoprotection - drug effects; Development and progression; Diabetes; Diabetes Complications - blood; Diabetes Complications - genetics; Diabetes Complications - metabolism; Diabetes Complications - pathology; Diabetes mellitus; Drinking water; Extracellular matrix; Fasting - blood; Fibroblasts; Fibronectin; Fibrosis; Gelatinase A; Gene expression; Gene Expression Regulation, Enzymologic - drug effects; Genetic aspects; Glucose; Glycated Hemoglobin A - metabolism; Growth factors; Health aspects; Heart; Heart diseases; Hemoglobin; Hydrolases; Hydroxyproline; Hypertension; Insulin; Insulin - blood; Interleukin-1beta - metabolism; Kinases; Laboratory animals; Male; Matrix Metalloproteinase 2 - genetics; Matrix Metalloproteinase 2 - metabolism; mRNA; Myocardial diseases; Myocardium - metabolism; Myocardium - pathology; Naphthols - pharmacology; pH effects; Pharmacy; Rats; Rats, Wistar; Reduction; Rodents; Sirtuin 1 - antagonists & inhibitors; Sirtuin 1 - metabolism; Sodium; Sodium citrate; Streptozocin; Streptozocin - adverse effects; Transforming Growth Factor beta - metabolism; Tumor Necrosis Factor-alpha - metabolism; Tumor necrosis factor-TNF; Tumor necrosis factor-α
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0114560

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. 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. 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. 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.