| Objective Autoimmune myocarditis is a fatal disease, which has the main characteristics of myocardial systolic function invasion damage, heart enlargement and heart failure. Viral infection and autoimmune myocardial damage are important factors in pathological damage, there is no effective treatment currently. In autoimmune myocarditis, inflammatory cell infiltration, myocardial necrosis, fibrosis and further aggravating the development of dilated cardiomyopathy lead to heart failure eventually. Myocardial protein (CM) is an major autoantigen in autoimmune myocarditis and viral myocarditis. Exogenous myocardial protein immunized rats is the common disease model of autoimmune myocarditis, which is mediated by CD4+T cell. N-acetyl-serine-aspartic-lysyl-proline (AcSDKP) is an endogenous anti-inflammatory and anti-fibrotic peptide, its precursor is thymosin beta4. It presents in plasma and tissues in human body. AcSDKP is known to be the proliferation inhibitors of hematopoietic stem cell. It is storaged and synthesized in the bone marrow, then released to the blood, heart, liver, kidney, testis and other tissues and organs. It can be detected in human peripheral blood mononuclear cells and urine. AcSDKP is hydrolyzed by angiotensin converting enzyme (ACE), the plasma concentration will be increased significantly after angiotensin converting enzyme inhibitor (ACEI) being added. ACEI can reduce EAM mortality and the delayed hypersensitivity reaction. We hypothesis that in EAM, AcSDKP prevents cardiac remodeling and dysfunction by modulating the immune system.Methods Lewis rats were immunized with porcine cardiac myosin and treated with AcSDKP or vehicle. Systolic blood pressure was measured in conscious rats by use of a noninvasive computerized tail-cuff system weekly, heart ultrasound was detected at the beginning and the end of the experiment, then rats were killed, blood plasma, spleen and heart were collected. At the end points of the study, rats were euthanized and the abdomen opened. The kidney was excised, the capsule was removed and weighed, and the ratio of kidney weight:body weight (BW) was determined. It was then sectioned transversely into4sections. One section from the middle of the kidney was fixed in4%paraformaldehyde for a paraffin-embedded section. A lower midrenal section was embedded in optimal cutting temperature compound and immersed in cold isopentane (VWR), then snap-frozen in liquid nitrogen and stored at-80℃. The T lymphocytes of the spleen were detected by flow cytometry. Cytokines in plasma such as TNF-a, IL-1β, and IL-17expression were detected by Enzyme linked immunosorbent assay (Elisa) or Western blots.Results (1) In EAM, Ac-SDKP improved systolic and diastolic dysfunction and decreased cardiac hypertrophy, inflammation, and fibrosis.(2) AcSDKP also prevented inflammatory cell infiltration (macrophages, dendritic cells, and T helper lymphocytes), expression of innate (TNF-a, IL-1β) and adaptive (IP-10, IL-17) immune cytokines, delayed type hypersensitivity, and Concanavalin A-induced lymphocyte proliferation.(3) In Lewis normal control rats, there had no differences in AcSDKP treatment and vehicle.Conclusions In EAM, AcSDKP prevents cardiac inflammation and fibrosis that ultimately may improve cardiac hypertrophy and function. These protective effects of AcSDKP are accompanied by the suppression of innate and adaptive immunity which may protect against inflammation and autoimmunity. Objective Salt plays a significant role in the genesis of hypertension. Dahl Salt Sensitive rats (DSS) rats is a commomly used model of human salt sensitive hypertension. Hypertensive Dahl SS rats are inclined to have end in organ injury (EOD) including kidney and heart. Acetyl-Ser-Asp-Lys-Pro (Ac-SDKP), a naturally occurring tetrapeptide, hydrolyzed mainly by angiotensin converting enzyme (ACE), reduces cardiovascular and renal inflammation and fibrosis, and improves renal function in various model of hypertension. The pathogenesis of EAM is mainly mediated by Th lymphocyte. Our previous experiments showed that AcSDKP has obviously protective effect on EAM rats through the innate and adaptive immune regulation, AcSDKP can inhibit inflammatory reaction and fibrosis of the heart, and reduce cardiac remodeling and dysfunction. At the same time in deoxycorticosterone acetate (DOCA) hypertensive rats and5/6nephrectomy rats, AcSDKP can improve renal function and inhibit renal fibrosis. However, we have not tested whether Ac-SDKP has similar beneficial effects on Dahl SS hypertensive model.Methods Male Dahl Salt Sensitive rats (DSS)8weeks of age were fed a diet containing either0.23or4%NaCl and divided into2groups:1) vehicle,2) Ac-SDKP (800μg/kg/day) infused by osmotic minipump. After6weeks of treatment, the heart was excised, the capsule was removed and weighed, and the ratio of heart weight:body weight was determined. It was then sectioned transversely into3sections. One section from the middle of the heart was fixed in4%paraformaldehyde for a paraffin-embedded section. A lower section was embedded in optimal cutting temperature compound and immersed in cold isopentane, then snap-frozen in liquid nitrogen and stored at-80℃. Systolic Blood Pressure, cardiac and renal function, pathology, infiltration of inflammatory cells (macrophages and CD4+) were also studied.Results In the model of DSS hypertensive rats, AcSDKP does not decrease systolic blood pressure and glomerular filtration rate. AcSDKP can obviously reduce the urinary albumin, inhibit macrophages, dendritic cells and Th lymphocytes and other inflammatory cells’infiltration in the kidney, and ultimately reduce renal inflammation and fibrosis.Conclusion In DSS rats, AcSDKP can reduce urinary protein, renal fibrosis, but AcSDKP can not lower systolic blood pressure, it can not improve the glomerular filtration either. Objective AcSDKP is a trtrapeptide produced in bone marrow and distubutes aroud the tissure and blood, it is also a cytokine which inhibits cell proliferation. AcSDKP can stimulate neovessels especially tumor vessel. It is overexpressed in human breast cancer, head and neck cancer, renal cancer, pulmonary cancer, canceroderm, ovarian cancer and prostatic cancer, it is also overexpressed in AML in plasma and even higher in MDS patients. It can inhibits monocyte, macrophage and cytokines invasion as PDGF, ET-1, MMPs, to suppress the proliferation of f ibroblasts and the formation of collagen. Via downregulating the downstream regulating factor of TGF-β Smads to impact the activity of NF-K B, AcSDKP inhibits the formation of collagen to lighten the fibrosis of tissures and organs. Because of the action of inhibiting cell prolifetaion, it can protect stem cell during chemotherapy. VEGF is a kind of cytokine which can react with vascular endothelial cell, stimulate vascular endothelial cell proliferation and migration, increase the vascular permeability, and induce the neovessels. So it has an important role in the leukomogenesis and metastasis. Based on the study of the first and second parts of our work, we will discuss the relativity between the expression of AcSDKP and the vascular endothelial growth factor level in children’s acute leukemia in this part.Methods Blood samples were collected from childhood acute leukemia. AcSDKP and Vascular Endothelial Growth Factor expression were measured using enzyme-linked immunosorbent assay (Elisa). We studied the effect of AcSDKP in childhood acute leukemia.Results The AcSDKP and VEGF levels of childhood acute leukemia were higher than normal control. After the patients achieved complete remission, the concentration of AcSDKP and VEGF decreased to normal. This suggests that angiogenesis have an important role in childhood acute leukemia. AcSDKP may promote the angiogenesis in these patients. We also found that the plasma levels of AcSDKP and VEGF in two cases of primary myelofibrosis expression were lower than those of normal children. This suggests that the role of angiogenesis is different in these diseases. |
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