| 摘 要： | Objectives To explore changes of myocardial pro-inflammatory and fibrogenic cytokines after coronary microembolization (CME) in rats. To observe effects of carvedilol at different doses on myocardial cytokines expression and ventricular remodeling. Methods A rat model of CME was created by injecting a suspension of microthrombotic particles generated from rat clots into left ventricle when clamping the ascending aorta. Forty SD rats were randomly divided into 4 groups(n=10 per group): sham-operation group(SO), CME group(ME), low-dose carvedilol intervention group (LCAR,1.0 mg·kg-1·d-1) and high-dose carvedilol intervention group (HCAR, 10.0 mg·kg-1·d-1). A microscopy incorporated with an image analysis software was employed to calculate the number of micro-myocardial infarction (Nmmi) and the area of micro-myocardial infarction (Ammi) in sections with HE-staining, to measure the collagen volume fraction(CVF) in sections with Sirius-Red-staining, to detect the density of expressions of TNF-α, IL-1β, TGF-β1 and MMP-9 in sections with immunohistchemical staining, to calculate the myocyte apoptosis rate (Rapo) in sections with TUNEL-staining. Two-dimensional Echocardiography was performed to monitor left ventricular end-diastolic diameter (LVEDD) and end-systolic diameter (LVESD), left ventricular fraction shortening (LVFS) and ejection fraction (LVEF); and electrophysiolography was utilized to measure left ventricular systolic pressure(LVSP), maximal positive dp/dt ( LVdp/dtmax), and end diastolic pressure(LVEDP). Four weeks after operation, comparing measurements in ME with those in SO, both Nmmi and Ammi were increased(P<0.01, each); all of the expressions of TNF-α, IL-1β, TGF-β1 and MMP-9 were increased (P<0.01,each), both CVF and Rapo were increased (P<0.01,each), both LVEDD and LVESD were increased but LVFS and LVEF were reduced(P<0.01,each), both LVSP and LVdp/dtmax were increased (P<0.01,each), but LVEDP was increased (P<0.01). Comparing with measurements in ME, the expression of TNF-α, IL-1β, TGF-β1 and MMP-9 were decreased(P<0.01,each), both CVF and Rapo were decreased(P<0.01,each), LVEDD and LVESD were smaller(P<0.01,each), LVEF and LVFS was higher(P<0.01,each), LVdp/ dtmax were increased and LVEDP was decreased(P<0.01,each), heart rate were slower (P<0.01,each) both in LCAR and HCAR. Except for LVSP, the above-mentioned changes were more remarkable in HCAR than in LCAR(P<0.05). Myocyte interstitial CVF was positively correlated with the expression of IL-ip and TGF-β1(r=0.81 and 0.93, P<0.01), the activity of MMP-9 was obviously positively correlated with the expression of TNF-αand IL-β1(r=0.90 and 0.91, P <0.01), and Rapo was positively correlated with the expression of TNF-α(r=0.88, P<0.01). Conclusions Left ventricle is undergoing progressive remodeling after CME due to abnormal expressions of pro-inflammatory and fibrogenic cytokines leading to myocyte apoptosis and interstitial collagen proliferation. Via down-regulating the expressions of these cytokines, Carvedilol intervention decreases myocyte apoptosis, interstitial collagen proliferation and improve ventricular function.
|
