Abstract
Background: Little information is currently available concerning the relative contribution of cardiac parenchymal and stromal cells in the activation of the pro-inflammatory signal cascade, at the initial stages of diabetes. Similarly, the effects of early resveratrol (RSV) treatment on the negative impact of diabetes on the different myocardial cell compartments remain to be defined. Methods: In vitro challenge of neonatal cardiomyocytes and fibroblasts to high glucose and in vivo/ex vivo experiments on a rat model of Streptozotocin-induced diabetes were used to specifically address these issues. Results: In vitro data indicated that, besides cardiomyocytes, neonatal fibroblasts contribute to generating initial changes in the myocardial environment, in terms of pro-inflammatory cytokine expression. These findings were mostly confirmed at the myocardial tissue level in diabetic rats, after three weeks of hyperglycemia. Specifically, monocyte chemoattractant protein-1 and Fractalkine were up-regulated and initial abnormalities in cardiomyocyte contractility occurred. At later stages of diabetes, a selective enhancement of pro-inflammatory macrophage M1 phenotype and a parallel reduction of anti-inflammatory macrophage M2 phenotype were associated with a marked disorganization of cardiomyocyte ultrastructural properties. RSV treatment inhibited pro-inflammatory cytokine production, leading to a recovery of cardiomyocyte contractile efficiency and a reduced inflammatory cell recruitment. Conclusion: Early RSV administration could inhibit the pro-inflammatory diabetic milieu sustained by different cardiac cell types.
Highlights
The occurrence of ventricular dysfunction independent of coronary artery disease, hypertension and valvular or congenital heart disease has been recognized for over 40 years in both type 1 and type 2 diabetes [1]
The changes in cytokines induced by high glucose increased only in Neonatal Cardiomyocytes (nCMs) culture media (Figure 2b)
Our study suggests the initial changes stages of (i) interstitial cells ininaddition pro‐inflammatory cytokine production; (ii) alterations in the myocardial tissue environment are of cardiomyocytes promote early unfavorable changes in the myocardial diabetic milieu, in terms of abnormalities in cardiomyocyte associated with initial damage and the occurrence pro-inflammatory cytokine production; (ii) alterations in the myocardial tissue environment are contractile properties, in the absence of left ventricular (LV) structural damage or collagen accumulation; (iii) RSV
Summary
The occurrence of ventricular dysfunction independent of coronary artery disease, hypertension and valvular or congenital heart disease has been recognized for over 40 years in both type 1 and type 2 diabetes [1]. Many efforts have been made to test novel therapeutic strategies aimed at preventing these early detrimental changes in the diabetic heart In this context, a growing body of evidence supports that administration of low doses of resveratrol (RSV: trans-3,5,40 -trihydroxystilbene), a polyphenolic compound and naturally occurring phytoalexin, may prevent the occurrence of DCM [7,9,10,11,12]. It has been shown that besides its antioxidant, antiapoptotic and anti-inflammatory effects, RSV possesses several other cardio-protective roles due to a large array of direct and indirect target molecules mediating its biological actions These include modulation of enzyme activity, cell signaling pathways and gene expression [9,10,11,12,13,14,15]. The effects of early resveratrol (RSV) treatment on the negative impact of diabetes on the different myocardial cell compartments remain to be defined
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