| PART ONE: THE STUDY OF THROMBOPOIETIN PROTECTS AGAINST DOXORUBICIN INDUCED CARDIOTOXICITY AND ITS MOLECULAR MECHANISM IN RATSObjective:To investigate the effect of thrombopoietin (TPO) protects against doxorubicin (DOX) induced cardiotoxicity in a rat model and its potential molecular mechanism.Methods: In the acute model of cardiomyopathy, male SD rats were divided into 4 groups:DOX (n = 6), DOX+TPO (n = 6), Control (n = 5) and Control+TPO (n = 5), the animals were sacrificed at the end of day 5. In the chronic model of cardiomyopathy, rats were divided into 3 groups:DOX (n = 17), DOX+TPO (n = 14) and Control (n = 14), the animals were sacrificed at the end of week 6. The body weight, cardiac function, peripheral blood cells were measured. For the acute rats, RNA expression was measured by the whole genome Agilent microarray system.Results:1. DOX can induce body weight loss: in the acute model, body weight decreased 24 hours after a single dose of DOX at 17.5mg/kg; in the chronic model, DOX was injected at 2.5mg/kg weekly for 6 weeks, in the week 1, body weight fell behind the control group (P = 0.000), in the week 5, body weight began to decrease. TPO treatment had no significant effect on body weight.2. In the chronic model, DOX significantly decreased WBCs (P = 0.000) and RBCs (P = 0.000). TPO treatment had no significant effect on peripheral blood cells.3. DOX treated animals had compromised heart function. Both in acute and chronic models, LVEDD (P = 0.006 and P = 0.003), HR (P = 0.006 and P = 0.001), FS (P = 0.045 and P = 0.005) and CO (P = 0.006 and P = 0.000) significantly reduced. TPO can improve cardiac function in terms of FS (P = 0.007) and EF (P = 0.010) in chronic rat models.4. Comparing with the Control, 5056 transcripts were up- or down-regulated over 2-fold after DOX treatment, whereas 3490 transcripts were differentially expressed between DOX and DOX + TPO groups. Of the two comparisons, 1229 transcripts were overlapping, of which 93.2% were regulated at an inverse manner. The biological process ontologies influenced by TPO included inflammatory response, apoptosis, cell differentiation and tissue remodeling for up-regulated targets; and ubiquitin cycle, cell activation and tissue morphognesis for down-regulated targets.Conclusion:TPO protects against DOX-induced cardiac function injury both in acute and chronic rat models. Regulation of genes relevant to heart functions at an inverse manner might contribute to the protective effect.PART TWO: THE STUDY OF CARDIOPROTECTIVE EFFECT OF THROMBOPOIETIN IN A RAT MODEL OF MYOCARDIAL INFARCTION AND ITS MECHANISMObjective:To investigate the cardioprotective effect of thrombopoietin (TPO) in a rat model of myocardial infarction (MI) and its potential mechanism.Methods: Male SD rats were divided into 4 groups: SHAM (n = 9), MI (n = 11), MI+TPO (n = 13) and TPO (n = 9). MI animals were subjected to left anterior descending coronary artery ligation. The animals were sacrificed at the end of week 4. TPO was administered at 10ug/kg intraperitoneally 3 times a week for 2 weeks. The body weight, cardiac function, peripheral blood cells, myocardial ultrastructure, bone marrow-derived endothelial progenitor cells (EPCs) were measured.Results:1. Rats had compromised heart function 4 weeks after MI, as demonstrated in LVEDD (P = 0.000), LVESD (P = 0.000), HR (P = 0.02), FS (P = 0.000) and EF (P = 0.000). Myocardial ultrastructure was severely damaged.2. TPO treated animals had decreased LVEDD (P = 0.031) and LVESD (P = 0.004), and significant improvement in FS (P = 0.005) and EF (P = 0.005) compared with the MI group. TPO alleviated myocardial ultrastructure damage, and TPO treatment had no significant effect on peripheral blood cells.3. TPO significantly increased bone marrow-derived EPCs (P = 0.005). Bone marrow-derived EPCs can be cultured in vitro expressing specific surface markers with normal functions.Conclusion:TPO can significantly improve cardiac function in a rat model of MI and reduce myocardial damage, which may be related to the proliferation of bone marrow-derived EPCs. PART THREE: THE STUDY OF CARDIOPROTECTIVE EFFECT OF DEXRAZOXANE IN A RAT MODEL OF MYOCARDIAL INFARCTION AND ITS MECHANISMObjective:To investigate the cardioprotective effect of dexrazoxane (DZR) in a rat model of myocardial infarction (MI) and its potential mechanism.Methods: Male SD rats were randomly divided into four groups: MI (n=16), MI+DZR (n=16), SHAM (n=14) and DZR (n=9). MI animals were subjected to left anterior descending coronary artery ligation. DZR was administered as a single dose at 125mg/kg intraperitoneally. Four weeks after treatment, cardiac function by echocardiography, infarct size, capillary density in the infarct border zone, bone marrow-derived endothelial progenitor cells (EPCs), and cardiac expression of Bax were measured.Results:1. Rats with MI had increased heart weight (P = 0.000) and lung weight (P = 0.000). DZR treated animals had significantly lower lung weight (P = 0.015).2. At 4 weeks post-MI, compromised heart function was observed in the MI animals compared with the SHAM group, as demonstrated in LVEDD (P < 0.001), LVESD (P < 0.001), FS (P < 0.001) and EF (P < 0.001). Treatment with DZR saw decreased LVEDD (P = 0.012) and LVESD (P = 0.009), and significant improvement in FS (P = 0.004) and EF (P = 0.004) compared with the MI group.3. Left ventricular infarct size was significantly reduced in the MI+DZR group at week 4 compared with the MI group (20.5% vs 35.5%, P = 0.013), The ratio of the thickness of the infarcted wall to the non-infarcted septal wall was significantly higher in the MI+DZR group compared with that of the MI group (0.409 vs 0.743, P = 0.000).4. DZR significantly increased bone marrow-derived EPCs (P < 0.05) and capillary density in the infarct border zone (P = 0.008), and reduced protein expressions of Bax.Conclusion:Our study demonstrated that DZR exerted a cardioprotective effect in the rat model of MI, and the mechanisms might be associated with reducing Bax expression levels of myocyte apoptosis and proliferation of bone marrow-derived EPCs for neovascularization.
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