An Experimental Study On The Impact Of Acute Pulmonary Embolism To Brain Natriuretic Peptide And Natriuretic Peptide Receptor C

1. Background and PurposePulmonary embolism is a kind of relatively common cardiovascular emergency whichresults from the blocade of the pulmonary arteries and their branches by venousthrombi or atherosclerotic plaques, tissue fragments or other matters entering into thevenous circulation such as the tumor, fat, air and other foreign bodies. In accordancewith the progression of the disease, it is defined as aucte or chronic pulmonaryembolism which is accompanied by dyspnea or other discomforts. The diagnosis canbe made through electrocardiogram, blood biomarkers or radiological imagingtechnologies. Meanwhile, brain natriuretic peptide, as a new candidate of biomarkers,has also provided a supplementary of above diagnostic methods and been graduallyused to evaluate PE clinic outcome and treatment.Brain natriuretic peptide is mainly produced by the cardiac myocytes where theirrelease can be enhanced by increased vascular tension and closely related toventricular dysfunction. Together with atrial natriuretic peptide (ANP) and C typenatriuretic peptide they play an important role in cardiorenal homeostasis: Theycirculate as hormones to act in various tissues in the body inducing not onlyvasodilation, natriuresis, and diuresis but also the inhibition of cardiac hypertrophy,fibrosis and apoptosis in myocardial cells where they show an end-organ activity.Although among acute pulmonary embolism patients its concerntration signifcantlyincreased, its high level don’t produce more corresponding target organ effects.Recent studies support the notion that HF patients actually manifest a state of BNPinsuffciency or resist to its effect where they actually play an important cardiovascularprotective hormone.C-type natriuretic peptide receptor, as the main clearance receptor in our bodies,has been paid more and more attentions, whose applications in the cardiovascularand cellular signal transduction fields gradually increased. Although its expression level was also found to be affected by many factors, a series of corresponding effectsfollowing APE are still not clear. Combined with the fact that BNP acts as a newbiomarker for APE and the changes of its concentration and function, it might berelevant with NPR-C receptor, which has not caused corresponding attention.We has established a mouse APTE model and observed the changes of NPR-Clevels in vivo. By comparing with the alternations of BNP concerntraion, we aimed tofind their correlation, and to explore the possible mechanisms which regulate theirexpressions. This study lay the foundation for our further research on pathologicalmechanism of pulmonary thromboembolism, screening of drugs, and provided auseful train of thought for furture clinical diagnosis and treatment.2. Methods1. By comparing with the whole blood induced pulmonary embolism models, tryto modify and establish a more steady mouse APTE model. Through HE staining andPTAH staining of sections of lungs, monitoring BP and PAP, testing TNF-α level, wehave evaluated the advantages and disadvantages of these models.2. By DAB staining, distributions of NPR-C in lung were shown; By westernblotting and PCR technology, changes of protein level and mRNA level of NPR-Cwere tested; EIA kit and PCR were also used in the tests of BNP plasmaconcerntration and mRNA levels.3. Elisa kit was used to test the levels of endothelin-1(ET-1) and cardiac troponinI (cTnI) following induced mouse APTE.3. Results1. HE and PTAH staining have proved its reliable embolism whose most embolilay in the level of segments or subsegments of pulmonary arteries. White-autologousthrombi pulmonary embolism model showed no obvious fibrinolysis of the thrombi (5%and30%separately in24h and48h), while whole blood induced PE model showed a100%fibrinolysis of the thrombi. Mice following pulmonary showed significantdyspnea and decrease of BP, obvious increased PAP, and significantly reducedpostoperative activity.2. IHC staining suggested that NPR-C expressed widely in pulmonary tissues,and its distribution density gradient between different tissues chaned significantlyfollowing PE. 3. Western blotting showed that NPR-C proteins decreased significantly afterAPTE in heart and lung, while there were no differences in kidney.4. RT-PCR proved that BNP was not expressed in lung and kidney; BNP mRNAlevels have significantly been down-regulated after APTE in heart and lung, but nodifferences were seen in kindney.5. BNP concerntration in plasma increased significantly, but the degree of itsincrease is greater than the degree of mRNA increase.6. No significant relations between PE and TNF-α were seen except for thestimulation resulted from the surgery operation; ET-1and cTnI increased significantly,and the latter one showed more greater changes.4. Conclusions1. The obvious fibrinolysis of the thrombi in white-autologous thrombi pulmonaryembolism models was largely improved than in the whole blood group; No obviousinflammation was seen resulted from the in vitro operated thrombi, and the mainsymptoms after PE was in line with the actual situations. In all, our model can bettersimulate the pathophysiological processes of APE which showed an obviousadvantages in scientific researches.2. NPR-C was down-regulated in mice following APE, which mainly existed inheart and lung, and the changes in lung mainly exited in pulmonary arteries. Theincreased plasma BNP resulted not only from the increased secretion but from thedecreased clearance.3. The mechanisms of NPR-C regulation were probably associated with thevascular mechanical tension.4. BNP combined with cTnI probably shows greater value in the diagnosis ofshort period after PE, while combined with ET-1in longer period after PE.