Abstract
BackgroundL-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.MethodsMale 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.ResultsL-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.ConclusionCollectively, 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.
Highlights
Diabetes mellitus (DM) is projected to embrace 439 million by 2030 [1]
Male Wistar rats were allocated into five groups; (i) normal control rats received 0.1 M sodium citrate buffer; (ii) STZ at the dose of 60 mg/kg dissolved in 0.1 M sodium citrate buffer; (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
Persistent hyperglycemia is pivotal in the incidence of diabetic cardiomyopathy (DCM), which is typically designated by increased cardiac cytokine [4, 5], inflammation, apoptosis as well as changes in the composition of the extracellular matrix (ECM) with enhanced cardiac fibrosis [2, 3, 5, 6]
Summary
Diabetes mellitus (DM) is projected to embrace 439 million by 2030 [1]. Noteworthy, cardiovascular diseases mount to three quarters of the deaths among population [2, 3]. One of the profibrotic cytokines that stimulate ECM protein production is the transforming growth factor-b- (TGF-b); which in the heart, triggers cardiac fibroblasts to differentiate into the more active connective tissue cells known as myofibroblasts [11]. These myofibroblasts are capable of producing up to twice as much collagen as their fibroblast precursors [12]. L-ARG protected against myocardial cellular death by reduction in NFk-B mRNA as well as TNF-a level in association with decline in Casp-3 and FAS expressions andCasp-3protein content in addition to reduction of FAS positive cells. 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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