Oxidative Stress Triggers Cardiac Fibrosis in the Heart of Diabetic Rats

Abstract

Diabetic cardiomyopathy is characterized by myocyte loss and myocardial fibrosis, leading to decreased elasticity and impaired contractile function. The study examines the downstream signaling whereby oxidative stress, induced by hyperglycemia, leads to myocardial fibrosis and impaired contractile function in the left ventricle of diabetic rats. It also examines the effects of dehydroepiandrosterone (DHEA), which prevents the oxidative damage induced by hyperglycemia in experimental models. DHEA was administered for 6 wk in the diet [0.02%, wt/wt)] to rats with streptozotocin-induced diabetes. Oxidative balance, advanced glycated end products (AGEs) and AGE receptors, transcription factors nuclear factor-kappaB and activator protein-1, and profibrogenic growth factors (connective tissue growth factor and TGFbeta1) were determined in the left ventricle of treated and untreated streptozotocin-diabetic rats. Structural and ultrastructural changes, and the contractile force developed by electrically driven papillary muscles, under basal conditions and after stimulation with isoproterenol, were also evaluated. Oxidative stress induced by hyperglycemia increased AGEs and AGE receptors and triggered a cascade of signaling, eventually leading to interstitial fibrosis. DHEA treatment, by improving oxidative balance, counteracted the enhanced AGE receptor activation and increase of profibrogenic factors and restored tissue levels of collagen I, collagen IV, and fibronectin to those of control animals. Moreover, DHEA completely restored the contractility of isolated papillary muscle. Oxidative stress led to cardiac fibrosis, the most important pathogenetic factor of the heart's impaired functional integrity in diabetes. Structural and ultrastructural changes and impairment of muscle function induced by experimental diabetes were minimized by DHEA treatment.

Involvement of RhoA/ROCK in myocardial fibrosis in a rat model of type 2 diabetes

“…These findings are in agreement with other studies [26][27][28] . Consistent with their impaired cardiac function, diabetic rats developed myocardial fibrosis, the marked fibrotic regions (as observed by immunohistochemical staining), as well as deposition of collagen fibers in the interstitial spaces among cardiomyocytes (as observed by TEM), our observations are similar to those described in other reports [29,30] . Increased myocardial fibrosis is a major factor responsible for myocardial stiffness and eventual systolic [31,32] .…”

“…First, to better understand the mechanism of action involved, cell culture study is needed to verify the causeeffect relationship with regards to the role of these signaling molecules in diabetic cardiac fibrosis. Second, it is known that diabetic cardiomyopathy is associated with significant increased oxidative stress which could lead to JNK activation and increased TGFβ [29,44] , so the contents of oxidative stress in the heart should be described. Third, there are only small number of rats in the study, this maybe limits statistical power and their results.…”

Alpha-Lipoic Acid Improves Subclinical Left Ventricular Dysfunction in Asymptomatic Patients with Type 1 Diabetes

“…In the heart, TGF-β induces the differentiation of cardiac fibroblasts to the more active myofibroblasts, which can produce up to two-fold more collagen than their fibroblast precursors [34]. The increased expression of TGF-β in our diabetic patients is consistent with animal studies that showed upregulation of TGF-β mRNA in the hearts of diabetic animals [7,35].…”

“…Hyperglycemia and oxidative stress activate NF-κB, which regulates the expression of large numbers of genes including pro-inflammatory cytokines (TNF-α and IL-1β) and several genes correlated to fibrosis, including TGF-β, in the diabetic heart [7,36]. ALA can scavenge intracellular free radicals and therefore down-regulate proinflammatory redox-sensitive signal transduction processes including NF-κB activation [28,29].…”

“…Collagen accumulation in the diabetic myocardium may be due to either excessive production by fibroblasts or decreased degradation by matrix metalloproteinases (MMPs). Hyperglycemia and oxidative stress cause abnormal gene expression which alters signal transduction, notably activation of NF-κB, which causes upregulation of several genes correlated to fibrosis, such as transforming growth factor-β (TGF-β), in diabetic heart [7].…”