| Atherosclerosis is a complicated chronic inflammatory and vascular disease. Plaque rupture leads to acute coronary syndrome (ACS), myocardial infarction or stroke, which threat to human health. The mechanisms are only poorly understood. Searching the potential drugs to improve outcomes in atherosclerosis is the main task to scientists.Numerous of data demonstrate that platelets are crucial players in this pathological process. Hypercholesterolemia increased adhesion of platelets to endothelium. The chemokines and cytokines released by activated platelets feed the inflammatory response, attracting monocytes and neutrophils, and then facilitating their migration into atherosclerotic lesion and finally promote the development of atherosclerosis.Anti-apoptotic factor Humanin is a24amino acid peptide originally isolated from brains of patients with Alzheimer disease. Earlier studies focused on its ability to suppress neuronal cell death induced by Alzheimer disease-related protein such as amyloidβpeptides. Recently, other studies have revealed that Humanin has a broader spectrum of protective activity. It provides cardiac myocyte or brain cell protection in a mouse model of myocardial or cerebral ischemia and reperfusion. The current study suggests that Humanin may play a role and may have a protective effect in early atherosclerosis in humans. For instance it is expressed in the vascular wall and the carotid atherosclerotic plaques in Humans. In vitro studies exogenous addition of Humanin to endothelial cell cultures was shown to be effective against Ox-LDL-induced apoptosis. But the mechanism is not cleared. Particularly in hyperlipidemia and atherosclerosis we will detect whether Humanin can attenuate the adverse consequences of hyperlipidemia on platelets, plasma lipid contents and the plaque size. Objective:Here we test the hypothesis that Humanin will attenuate the adverse consequences of hyperlipidemia on platelets and show its plasma cholesterol lowering ability. Finally we will detect whether Humanin can reduce atherosclerotic plaque size and confer protection against the development of atherosclerosis.HNG was chosen because it is1000times more potent than normal Humanin. So HNG is more effective than Humanin in clinical research. HNG also be used in other studies for example the mouse model of myocardial or cerebral ischemia and reperfusion.Methods:1. Using LDLR-deficient mice on a high-fat diet (HFD), we established the mouse model of hyperlipidemia and atherosclerosis.2. Based on the hyperlipidemia mice model, we compared the platelet with or without daily intraperitoneal injection of HNG and examine the platelet aggregation in response to ADP.3. We obtained the venous blood of hyperlipidemia mice and compared the mice with or without daily intraperitoneal injection of HNG and measured the plasma lipid contents.4. By feeding on HFD three to six months, LDLR-deficient mice can generate plaque. The thoracic aorta plaque size was compared between the atherosclerosis mice and the mice by daily intraperitoneal injection of HNG.Results:1. Using LDLR-deficient mice on HFD, we detected that the plasma lipid contents of LDLR-deficient mice increased for one to three months and plaques were observed in mice for three to six months. So we successfully set the mouse model of hyperlipidemia and atherosclerosis2. In the setting of hyperlipidemia, HNG can suppress platelet aggregation in response to ADP. 3. Daily intraperitoneal injection of the HNG can lower plasma lipid profiles of HFD mice.4. HNG decreased atherosclerotic plaque size in the proximal aorta of LDLR-deficient mice fed on HFD.Conclusions:We conclude that HNG reduces the platelet hyperactivity in the setting of hyperlipidemia, lowers the plasma lipid contents, decreases atherosclerotic plaque size and confers protection against the development of atherosclerosis. Therefore Humanin may represent a novel agent for treatment of atherosclerosis disease. |
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