| Cardiovascular disease remains a leading cause of patient morbidity and mortality, and it has become a focal point in the domain of medicine. Despite significant advances in preventive medicine and myocardial protection, ischaemic heart disease (IHD) remains a significant cause of patient morbidity and mortality. It is now accepted that the precipitation of acute coronary syndromes and most of acute myocardial infarction often occured in patients who did not show critical stenoses, even through their ECG had obviously changing, such as depressed ST-T. This and other findings challenged the relevance of stenosis severity as a major pathogenetic determinant in ischemic heart disease. Thus, a large amount of research had been put forward to investigate further mechanisms, besides changes in plaque burden and stenosis severity, associated with the precipitation of ischemia. In the absence of a satisfactory explanation, these phenomena have been attributed to microcirculatory disorders. In IHD, it generally did not produce detectable intimal thickening or plaque formation in coronary microvessels, unlike the situation in large conduit coronary arteries. However, functional abnormalities were known to extend to the coronary microvasculature. Among putative mechanisms, great attention has been paid in the potential role of coronary microcirculation as a cofactor in many clinical manifestations of IHD.Recently, atherosclerosis has been suggested to be an inflammatory disease, and also, it is a consequence of a chronic inflammatory process induced by activation of macrophages, complement and T-lymphocytes. The complement system is an integral part of the body's humoral defense mechanism and also a primary mediator of inflammatory processes. In the recently decade, several studies implicated that activation of the complement system had been associated with the prelesional stages as well as the progression of atherosclerotic lesions. The complement system was composed of three pathways: the classical, alternative and lectin complement pathways. The alternative pathway was activated by interaction with the surface of microorganisms and consisted ofsix plasma glycoproteins. Properdin was a positive regulator of the alternative pathway. It circulateed in the serum as cyclic polymer (dimer, trimer, tetramer, etc) and played its role by binding and thereby stabilizing the inherently labile C3 and C5 convertase complexes (C3bBb and C3bnBb). Although properdin was present in plasma at concentrations of 4~6ug/ml, its physiological source is still unclear. Monocytes, T cells, and bone-marrow progenitor cell lines (HL-60, U-937, Mono Mac 6) could synthesize properdin while neutrophils (PMNs) could release properdin from intracellular stores after stimulation by Af-formyl-methionyl-leucyl-phenylalanine (fMLP) and TNFa. Despite the ability of monocytes and PMNs to release properdin they were unlikely to contribute significantly to its plasma level: monocytes depending on their limited numbers in blood and PMNs because the release of properdin followed cell degranulation and was thus a process more likely to occur at extravascular sites rather than in the circulation. Endothelial cells (EC) might represent an important source of complement proteins in plasma because of their strategic position at the inner surface of the vessel wall. Indeed, EC had been shown to express a number of proteins related to the complement system. However, properdin belongs to the complement components, which could not be detected in EC maintained under standard culture conditions. Exposure of EC to shear stress had been shown to modulate the expression of a wide range of genes involved in the regulation of several endothelial and vascular functions. Recently, Mauro Bongrazio reported the ability of shear stress-exposed EC to synthesize properdin. But the relation between properdin and changing of coronary microvessels still remained largely speculative. So studying the action of properdin in the occurrence and the progression of coronary heart disease (CHD) has important significance, even in the hand of its prevention.Hypercholesterolemia (HC) is a major risk factor for coronary atherosclerosis, has been associated with impairment in coronary vascular function and myocardial perfusion, preceding development of overt atherosclerosis and potentially leading to cardiac events. HC rat is a mature animal model to leading CHD, and we used it to study the changing of structure and function for coronary microvessels while CHD happened and was progressing. Also we hoped to find the action and regulation mechanisms of properdin, to supplement pathogenesis of CHD and to find a novel way to prevent it. This experimental study was composed of there parts: (1) Hypercholesterolemia rat models were established. (2) Theexpression of properdin in monocytes/lymphocytes was studied in blood of hypercholesterolemia rat models. (3) It was done to analyze shear stress-exposed SD rats cardiac microvascular endothelial cells as physiological source for plasma properdin. The main results are as follows:1. We have investigated the changing of plasma lipids on the hypercholesterolemia rat models. To extend the breeding cholesterol time, total cholesterol (Teh), LDL and APO-B were significantly increased, and HDLC was decreased in HC group rats. After breeding cholesterol 50 days, the HC rats had ischaemic heart impairment which made cTnl increased and it had positive correlation to Teh and LDLC. It suggested that HC could lead IHD happen. Plasma viscosity of HC group rats were increased significantly too, and erythrocyte deformability were decreased, so it cleared that our model were belong to mild hyperviscosity syndrome. Correlation analysis proved that it has relation with HC.2. As the cholesterol breeding goes on, the levels of SAP, DAP, LVSP, LVEDP and ±dp/dtmM had shown a tendency of descent in HC group's rats than in NC group's rats, and correlation study showed that these had a strongly close relationship with the concentration of Teh and APOB(P<0.05). The present data showed that the hypercholesterolemia had effect on the myocardial function. And the descent of the myocardial function have a strongly close relationship with the high level of cholesterol and APOB (P<0.05).3. As the cholesterol breeding went on, the MVD of myocardium showed an increasing tendency, and the thickness of the myocardial arteriole were thickening gradually by the time. It suggested that the supply of blood were not enough at the early stage of the hypercholesterolemia. It meant the lesion of myocardial ischemia had taken place. The structure and the function of the myocardium microvessel had changed.4. The present data showed that the hypercholesterolemia might influence monocytes/lymphocyte of spleen. It might reduce the number of monocytes/lymphocytic apoptosis and activate monocytes/lymphocyte in blood, then made it synthesis properdin increasing and amplificated the cascade action of complement.5. It was concluded that low laminar flow produced shearing force which might induce the cardiac microvascular endothelial cells to synthesize properdin, and suggested that the high level of cholesterol might induce the cardiac microvascular endothelial cells to synthesize properdin, too.6. By protease digestion, machine shearing and filtration, to isolate and culture rat cardiac microvascular endothelial cells, we had obtained high purity and production. Used collagen of rat's tail to pretreat Petri dish, the result was same as using Laminin did. The present data showed that CD31 was a specific marker to microvascular endothelial cells.By our study, not only could the changing of hemorheology and hemodynamics be discussed in hyperlipemia of CHD, and the monitoring way be provide during the progress of CHD, but also could the pathogenesis of CHD be understood, and a certification be provide for complement which had taken part in immunologic reaction in microvascular endothelial cells. In conclusion, it was suggested that the cardiac microvascular endothelial cells had ability to synthesize complement component in some special condition, which was related with hydrodynamics. This would provide a novel way to study the change of cardiac microvessel at the beginning and during the progression of CHD. |
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