| Hypertension is a chronic condition and characterized by high systemic circulation blood pressure.It is one of most common disorders and a risk factor for cardiovascular disease. The prevalence of hypertension is rising with age and considerable unmet medical need. Myocardial contractility, circulating blood volume and peripheral vascular resistance maintain the circulation blood pressure under the regulation of nerve-humoral system. Endothelium dysfunction plays a important role in the development of hypertension. Endothelium-dependent nitro oxide dysregulation is an important cause of the initiation hypertension. The NO subsequently trigger its bioactivity dependent of the following factors: (1) the activity of NOS in the endothelial cell, (2) the interaction with active oxidant, (3) the sensitivity of the vascular smooth cell.Insulin resistance is closely associated with hypertension. Diminished tissue sensitivity to the metabolic actions of insulin is a characteristic feature of insulin resistance, which leads to hyperinsulinism to meet the need of glucose metabolism. In normal concentration, insulin maintans vasodilatation depending on NO synthesis and realease, While hyperinsulinism stimulates ET expression and release. Insulin resistance reduces the ratio of NO/ET, which impair endothelial vasodilation and anti-embolism function .In the long run, insulin resistance results in vascular smooth cell proliferation and transposition.Less than 15% hypertension patients can be satisfiedly controlled by one type of anti-hypertension drug. The majority patients need more than one anti-hypertension medicines. The side-effects of anti-hypertension medicines have reduced their general application.While the new generation of medicines are effect with reduced side-effect, they are costly and can not meet the requirement for all people.Therefore, more effective and affordable stratagies are needed to control the prevalence of hypertention, in particularly non-drug treatment.Exercise has different effects on blood pressure. Low intensity exercises can reduce the high blood pressure and improve a series of dysfunction. Low intensity exercises not only reduce cardiac output, vascular resistance and the ratio of vein wall/lumen, but also enlarge venous volume and capillary bed, which reduce the ratio of circulation volume/vascular bed volume and reduce the high blood pressure.Insulin resistance may represent a key mechanism of the spontaneous hytertension in rats. Low intensity exercises improve insulin sensitivity at the levels of pre-receptor, receptor and post-receptor. Typically, insulin-dependent glucose usage is partialy dependent on increased insulin in blood flow and substrate delivery to tissues, Low intensity exercises increase skeletal muscle fiber I and capillary quantity, which increase regional blood flow. Low intensity exercises increase insulin receptors expression in skeletal cell, while increase receptor tyrosine phosphorylation, insulin receptor substrate tyrosine phosphorylation and phosphatidylinositol kinase activation, which improve insulin metabolic signal pathway. Low intensity exercises also increase GLUT4 gene transcription, translocate GLUT4 to epicyte which enhance skeletal cell uptake glucose. Low intensity exercises reduce adipocyte size, increase oxidation of carbohydrate and fatty acids. It also increase PPARγprotein in skeletal cell, which increase the gene expression related to the fatty acids transportation and oxidation. Continouse exercises upregulate the PGC-1 gene expression, suggesting that exercises play a important role in PPARγpost-transcriptional regulation .The expression and activation of PPARγmay reduce the blood pressure like ACEI.In insulin resistance conditions, insulin stimulated NO bioactivity is decreased (decreased endothelial NO synthase activation and increased NO destruction), and ET release of endothelial cells increased. Low-intensity exercise improve all aspects of insulin resistance, increasing insulin sensitivity effectively, reducing the high insulin levels, thereby increase endothelial NO synthesis and release, through the effect on NOS transcription and expression, probably attribute to the PPARγstimulated by low intensity exercise, the same as PPARγ agonist rosiglitazon.Exercise effectively stimulate NO synthesis through increasing NOS expression; Exercise also reduce plasma ox-LDL levels, which then reduce the injury of vascular endothelial and the inhibition of NO generation; It also increases the expression of HSP90,which will improve anti-apoptosis and anti-oxidation capacity of cells, HSP90 can further regulate cell activity and control the information transmission pathway, which will promote eNOS'synthesis and secretion and play a protective effect on vascular endothelium.eNO is an endothelium-derived factor, the basic substrate of NO synthesis is L-arginine and oxygen, NOS is the key enzyme in this reaction. NO plays a pivotal role in vascular endothelial function.It blocks monocyte adhesion to endothelial cells by inhibiting platelet aggregation and expression of adhesion molecule,in the mean time, NO also inhibit LDL oxidation and vascular smooth muscle proliferation. NO is considered as an anti-inflammatory factor mainly by inhibiting nuclear factor-ΚB (NF-ΚB) activity. is mainly its anti-inflammatory mechanism Since ox-LDL can increase the vascular endothelial NF-κB activity, NO inhibits LDL oxidation to further suppress NF-κB activity. In addition, NO may also inhibit the activity of NF-κB by inhibiting the expression of macrophage colony-stimulating factor (M-CSF), monocyte chemoattractant protein -1 (MCP-1) expression and cell adhesion molecules .NF-κB binds to the promoter or enhancer of cytokines genes at the specific NF-Κb binding sites, initiates or regulates the transcription of these genes. Most of inflammatory cytokines promoters involved in endothelial dysfunction contain NF-κB sites, including IL-1β, IL-6, IL8, intercellular adhesion molecule (ICAM-1), vascular cell adhesion molecule (VCAM). The shear stress of high blood pressure and increased peroxide can trigger the NF-κB activation in vascular endothelial cells, promoting the expression of ICAM-1, VCAM-1 and monocyte chemotactic factor (MCP-1), leading to the proliferation and infiltration of mononuclear cells, damaging endothelia cells, prompting the formation of atherosclerosis.Heat shock proteins have attrached considerable attention in recent years by their endothelial protective function. When Organisms are stimulated by harmful stimuli in the environment, they rapidly adapt the changes by produce a series of short-term metabolism.Some protein synthesis is temporarily reduced and the expression of certain proteins are selectively up-regulated. It is a self-protective mechanism for the cells to responsed to the outside stimuli.which is called the heat shock response.Heat shock proteins belong to the family of molecular chaperones and play an important role in the process of refolding misfolded protein and degradating protease. HSP70 is a kind of conserved protein, in addition to the above-mentioned molecular chaperone function, it also improve the cells tolerance to stress. HSP70 accumulas in the plaque and protects the vascular endothelium. Inducible heat shock protein 70 inhibits the activation of IKK and the degradation of IκB, thereby inhibits the expression of NF-κB, This may be the mechanisms underlying the endothelium-protective effect of HSP70. Exercise can significantly increase the expression of HSP70 by inducing heat shock transcription factor (HSF1) activation and there is a gender difference in exercise-induced increase in HSP70 protein.This project was to study the effect and mechanism of low-intensity exercise on reducing blood pressure while protecting the vascular endothelial. Using Nifedipine, the calcium channel blocker as a positive control drug, the effects of low-intensity exercise on blood pressure of SHR rats were studied, as well as the changes of insulin sensitivity, vascular endothelial function, NF-κB and HSP70.The results showed that:(1) low-intensity exercise significantly reduced blood pressure, SHR rats.(2) low-intensity exercise significantly reduced the level of insulin resistance in SHR rats.(3) It reduced high blood pressure in SHR rats while reducing the SHR rat vascular endothelial lesions.(4) It significantly increased the SHR rat aortic NOS expression and activity.(5) It significantly increased the SHR serum NO concentration.(6)It significantly reduced the SHR rat aortic expression level of NF-κB.(7) low-intensity exercise increased HSP70 expression in rat aortic SHR.(8) low-intensity exercise increased IL33 expression in rat aortic SHR.We found that low-intensity exercise training significantly reduced blood pressure in SHR rats, similar to nifedipine monotherapy.Low-intensity exercise training also reduced insulin resistance, thereby enhanced the expression of vascular endothelial NOS, significantly increased plasma NO levels, inhibited the expression of vascular endothelial NF-κB, reduced the degree of vascular endothelial lesions and reduced the incidence of cardiovascular complications. Therefore, physical exercise, an economic, convenient and effective method should be given particular attention both at the beginning of treating blood pressure also when using together with antihypertensive drugs.It was thought that atherosclerosis is resulted from large or medium-sized lipid deposition in arterial wall, now it has been realized that this is a process of inflammatiory process. A lot of circulation inflammatory markers are related to atherosclerosis. The inflammation in the atherosclerotic plaque leads to intravascular thrombosis and ischemic events in two ways. First, the endothelium covering the plaque shift from the anticoagulant state to the state of promoting thrombosision. This will induce the release of pro- inflammatory factors such as tumor necrosis factor (TNF), interleukin-1? (IL-1?) by the macrophages. Second, the release of MMP (including MMP2,3,9) mediated by T lymphocytes and macrophages results in the decay of the fibrous cap composed of elastin and collagen, leads to plaque instability and rupture. The expose of the internal necrotic lipid core and collagen to the blood leads to intravascular thrombosis and ischemic events.T cells recognize endougenous LDL antigen by T cell receptor before is one of the mechanisms leading to rapid progression of atherosclerotic plaque. It is well known that activated macrophages and ox -LDL are specific antigens which can stimulate the immune response and T cell proliferation. T cells recruit to the vessel wall via adhesion molecules and chemokines torecorganise the ox-LDL and HSP on the arterial wall, which will activate T cells in the local. The cytokines released by activated T cells stimulate macrophages, the key effect cells of atherosclerosis. Macrophages enter into the vessel wall with the facilitation of cell adhesion molecule which is up-secreted by the endothelial cells. Several interlukins and their receptors are associated with the atherosclerosis in this inflammatory process and play an important role, such as upregulating endothelial cell adhesion factor, activating macrophages and promoting smooth muscle cell proliferation. The experiments using gene knockout or transgenic mices found that some of the interleukins play a catalytic role in the artery atherosclerosis, while the other may serve as anti-atherosclerotic factors. interleukin-1 family is much important in this process.Interleukin33 was identified in 1995, It belongs to the IL1 family and is an anti-inflammatory factors in the process of atherosclerosis. IL-33 expresses in many tissues such as large or small vascular endothelial cells.IL-33 play a protective effect on atherosclerosis, by inducing the swithching from Th1 cells to Th2 , increase significantly serum levels of anti-atherosclerotic factors such as IL4, IL5, and IL13, increase the level of ox - LDL antibodies IgA, IgE, and IgG, which enhance anti-inflammatory effect, reduce the serum concentration of IFNγwhich can promote atherosclerosis.It also reduces the production of NF-KB induced by angiotensinⅡand phenylephrine to reduce arterial plaque inflammation. Recombinant IL-33 treatment can significantly reduce the atherosclerotic plaque. In this study the expression of IL-33 in coronary arterty specimens from 30 patients with different conditions were observed by immunohistochemistry, to further reveal the role of IL-33 in the process of human atherosclerosis. The results showed that IL-33 not only expressed in the human coronary artery intima and plaque, but also was correlated with the extent of atherosclerosis. Further study is needed to identify IL-33/ST2 signaling pathway inside the cells, which would contribute to the development of new cardiovascular protective drug.
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