Mice With Viral Myocarditis, Myocardial Matrix Metalloproteinases In The Role Of Myocardial Collagen Remodeling

Myocarditis is a common cardiovascular disease in clinical practice, which is one of themain reasons of sudden death. Usually, chronic myocarditis leads to dilated cardiomyopathy(DCM). Many researchers considered that virus infection is one of the primary causescontributed to myocarditis at present. About 50 percent of viral myocarditis (VM) cases areassociated with Coxsackievirus B (CVB) infection. The pathogenesis of VM is not clarifyedthoroughly and there are no effective therapies against VM so far. Therefore, it is very importantto exprole the pathogenesis and therapy of VM. The latest study indicated that abnormal matrixmetalloproteinases (MMPS) were involved in pathologic courses of cardiovascular dieases. Theexcessive expression and activity of MMPS or unfit MMPS/TIMPS proportion will inducemyocardial collagen decomposed and replaced by the fibrous matrix absent of connectivestructure, which can result in myocardial collagen remodeling, expansile ventricle, thin wall,heart failure or myocardial fibrosis. In addition, the study confirmed that local renin-angiotensinsystem (RAS) of heart was activated during the course of cardiovascular disease. As a maincontributing molecule, AngiotensinⅡ(AngⅡ) can accelerate the synthesis and hyperplasia ofmyocardial collagen, which was one of the important factor of myocardial collagen remodelingand myocardial fibrosis. AngⅡwas regulator of MMPS that regulating the expression ofMMPS/TIMPS. There were a few researchs indicated that the expression and activity of MMPSincreased in VM mice, and MMPS correlated with the changes of myocardial collagen intensely.But the changes of myocardial MMPS/TIMPS and the relationship of MMPS with myocardialcollagen remodeling were not knowed completely. By now, there is no any report about therelationship of myocardial MMPS with RAS in myocardial collagen remodeling of VM. In ourresearch, mice model of VM was established and fosinopril or valsartan was used to block RASat the levels of angiotensin converting enzyme(ACE) and angiotensin Ⅱtype-1 receptor( AT1-R)respectively. We detected the contents of AngⅡ, the expression of MMP-3 and TIMP-1 inmyocardium, myocardial collagen contents and the ratio of Ⅰ/Ⅲ. We explored the relationshipof MMPS with RAS and their effects on myocardial collagen remodeling elementarily. The studywill offer experimental reliance for treating VM with ACEI and AT1-R antagonists.The study contained three parts of investegation.Part one: The establishment of the mice model of CVB myocarditis. 80 purebredmale Balb/c mice' aged 4 to 6 weeks and weighted 18 to 20 grams, were divided into controlgroup(n=20) and model group(n=60) randomly. VM model was founded by injectingintraperitoneally 0.1ml CVB3 Nancy solution, while the control group was injected with 0.1mlHep-2 cell refrigerant solution excluding virus. All mice were feeded normally. The model micewere sacrificed by snipping carotids with aether anaesthesia on day 7, day 14, day 28 and day 42respectively after injecting CVB3. 0.8~1.0ml blood were extracted by burettes. The serums wereseparated and stored at 4℃, preparing for the test of virus counteracting antibody. Then all micewere killed by cutting necks, obtaining hearts and putting them into 4% formaldehyde solutionfor biopsy after blotting up blood with filter paper and being weighed. The twenty mice ofcontrol group were dealed with by the same methods on day 42. We found that the model micedisplayed tarnishable furs, reduced movements, been weary spirits and poor appetites, vaultedbacks, showed indifference to stimulation or tended to irritation and been lower temperaturesince the third day. Death occured on day 4, and reached the top from day 7 to day 10(14 micedied, the ratio was 66.7%). The symptoms mentioned above were alleviative gradually and nodeath happened from day 12. Among 60 mice in model group, 21 died. The death rate was 35%and the survival rate was 65%. None of the control mice had any symptom and death. Thelivability was 100%. The serum anti-CVB3 antibody concentrations of the model group...