The Role And Molecular Mechanism Of Se- And VE-deficient Diet On Myocardial Fibrosis And Remodel In Keshan Desease

Myocardial remodel is charactered by myocardial cell swelling, fibroblasts hyperplasia and myocardial fibrosis, combined with heart chamber expansion and heart weight increase. Myocardial remodel is the common end of a variety of myocardial injury and a major factor of refractory heart failure. Myocardial remodel was very evident in Keshan disease (KD), especially in children chronic type KD. Myocardial remodel is very fast in children chronic type KD, and the period from the onset, chronic course to death is no more than two to three years in common. This lead to a hypothesis that there are factors accelerate and increase myocardial fibrosis and cardiac remodel in the KD patients'living environment, especially in diet. In addition, natural chronic type KD is the main form of KD in present. The pathological process of natural chronic type KD is not completely clear. It was considered that natural chronic type KD display a small amount of scattered myocardial necrosis and apoptosis but not a large number of multifocal myocardial necrosis. Because of the acceleration and increasing factors for myocardial fibrosis, myocardial interstitial cell response actively, collagen accumulate and cardiac remodel. Therefore, we consider that acceleration and increasing factors for myocardial fibrosis in diet may play a particular important role on the development of natural chronic type KD.KD is a local cardiomyopathy caused by complex risk factor. The basic reason of KD regional distribution is selenium (Se)-and vitamin E (VE)-deficient diet caused by biogeochemical factors and dietary factors. There are other conditions factors are related to the occurrence of Keshan disease and rapid clinical disease, including protein-deficient diet, calcium-deficient diet, enterovirus infection and cereal mycotoxin infection. Se plays an important role in host antioxidant defense by virtue of its incorporation into the antioxidant enzyme GSH-Px as selenocysteine, GSH-Px is present in relatively high amounts within the heart. VE play an important role in the non-enzymatic antioxidant systems and has complementary, cooperative and mutual savings relationship Se. Se-and VE-deficient generally act on the ward people, the antioxidant defense were impaired in KD.Previous studies mainly focus on the role of Se-and VE-deficient diet on myocardial necrosis and clinical appearance of KD. The work about whether Se-and VE-deficient diet has persist influence on myocardial fibrosis and myocardial remodel after the occurrence of myocardial necrosis is rarely involved. We found that the relationship between Se-and VE-deficient diet and myocardial fibrosis and cardiac remodel is still rarely reported so far.According the previous research, we suppose that besides the cause of KD, Se-and VE-deficient diet may take part in the remoding process including break the net of collagen metabolism and accelerate the speed of myocardial fibrosis and myocardial remodeling. On the other hand, if enough Se and VE are added, the myocardial remodel would be decrease or reverse.In this study, morphology, biochemistry, immunohistochemistry, RT-PCR, Western blotting and other techniques were used. The rat myocardial fibrosis model was constructed by Se-and VE-deficient diet and isoproterenol injection. Suppose of whether Se-and VE-deficient diet play a continuing role in the repair process after myocardial injury and whether timely and adequate complementary Se and VE is able to reverse the excessive accumulation of myocardial collagen were investigated. In addition, the biological effects of Se and VE on myocardial fibrosis were verified through observing the effect of blocking the oxidative stress with Dehydroepiandrosterone (DHEA) on myocardial fibrosis induced by a Se-and VE-deficient diet.The main results are as follows:Wistar rats were feed with endemic grains (EG) or semi-synthetic grains (SG) for 81 d, the serum GSH-Px activity was decreased, the serum malonaldehyde (MDA) content was increased, myocardial cells displayed eosinophilic change, cell gap was widened, spotty necrosis and other changes were observed. On the basic of Se-and VE-deficient diet, the rats were injected with 10mg·kg-1 isoproterenol (ISO) to conduct myocardial fibrosis model. In the model group, the serum GSH-Px activity was decreased, the serum malonaldehyde (MDA) content was increased; the expression level of transforming growth factorβ1 (TGF-β1) and connective tissue growth factor (CTGF) were up regulatied, the expression level of matrix metalloproteinases-2 (MMP-2) and tissue inhibitors of MMP-2 (TIMP-2) were up regulatied, and the ratio of expression level between the MMP-2 and TIMP-2 were decrease; myocardial collogen was accumulated, myocardial fibrosis and myocardial remodel were observed. Supplementation Se and/of VE to the diet could alleviate these changes in different levels, lessen and reverse the myocardial fibrosis and myocardial remodel. We found that a Se-and VE-deficient diet induced myocardial lesions in rats, while DHEA caused a inhibition in the development of oxidative stress and collogen deposition in myocardial of the Se-and VE-deficient rats. In addition, DHEA counteracted activation of NFκB as well as the subsequent increase in TGFβ-1 and CTGF induced by the Se-and VE-deficient diet.In this paper we draw some conlusions as follows:(1) Se-and VE-deficient diet play a continuing role in the repair process after myocardial injury and accelerate the speed of myocardial fibrosis and myocardial remodeling.(2) Timely and adequate supplementation of Se and VE is able to reverse the myocardial fibrosis and myocardial remodeling.(3) The role Se and VE on myocardial fibrosis and myocardial remodeling may be complete through the following mechanisms:dietary supplementation with Se and/or VE can down regulate transforming growth factor-β1 and connective tissue growth factor expression in myocardial fibrosis rat, up regulate MMP-2 and TIMP-2 expression, increase the level of the ratio of MMP-2 and TIMP-2, inhibiting the excessive accumulation of collagen.(4) The biological effects of Se and VE on myocardial fibrosis were verified through the effect of blocking the oxidative stress with DHEA on myocardial fibrosis induced by a Se-and VE-deficient diet.Our results may be beneficial for controling the development of chronic KD, improving the prognosis of chronic KD, reducing the frequency of natural chronic KD, clarifying the relationship between Se/VE and a number of chronic degenerative diseases, such as pancreatic fibrosis, liver fibrosis, dilated cardiomyopathy, providing new ideas and theories for prevention and controling on organ fibrosis caused by these diseases.Innovation of this study: Verifying Se-and VE-deficient diet accelerate the speed of myocardial fibrosis and myocardial remodeling, timely and adequate supplementation of Se and VE is able to reverse the myocardial fibrosis and myocardial remodeling. This is a very important issue on prevention and controling the current KD, especially natural chronic KD.