Thirunavukkarasu Mahesh, Selvaraju Vaithinathan, Dunna Nageswara Rao, Foye Jocelyn L C, Joshi Mandip, Otani Hajime, Maulik Nilanjana
Department of Surgery, Molecular Cardiology and Angiogenesis Laboratory, University of Connecticut Health Center, Farmington, CT, USA.
Int J Cardiol. 2013 Oct 3;168(3):2474-80. doi: 10.1016/j.ijcard.2013.03.005. Epub 2013 Apr 13.
Statins (HMG-CoA reductase inhibitors), are known to improve cardiac function in diabetes-induced cardiovascular disease. We investigated the mechanism by which statins ameliorate cardiac function after myocardial infarction (MI). Simvastatin (S) increased tube formation and migration of HUVEC in vitro. We examined the role of simvastatin on cardiac function in streptozotocin (STZ) induced diabetic rats subjected to MI.
Rats were randomly assigned to 1) Control (non-diabetic) Sham (CS); 2) Control (non-diabetic) MI (CMI); 3) Control Statin treated Sham (CSS); 4) Control Statin treated MI (CSMI); 5) Diabetic Sham (DS); 6) Diabetic MI (DMI); 7) Diabetic Statin treated Sham (DSS); 8) Diabetic Statin treated MI (DSMI). Two weeks after STZ/saline injection Simvastatin (1mg/kg.b.wt) was gavaged for 15 days (d). MI was induced 30 d after treatment by permanent LAD ligation.
The S treated MI groups exhibited increased arteriolar density (23 ± 0.6 vs. 14.8 ± 0.4 counts/mm(2), DSMI vs. DMI) and reduced fibrosis at 30 d post-MI. VEGF measurement by ELISA after 4d post-MI showed increased expression in DSMI group compared to DMI group. Western blot analysis showed decreased Prolyl-4-Hydroxylase 3 (PHD-3) in DSMI group as compared to DMI group. Echocardiographic analysis 4 weeks after post-MI showed significant improvement in ejection fraction (50.11 ± 1.83 vs. 32.46 ± 2.19%; DSMI vs. DMI) and fractional shortening (26.77 ± 1.12 vs.16.36 ± 1.22%; DSMI vs. DMI) in both statin-treated MI groups regardless of diabetic status.
These results suggest that statin therapy mitigates impairment of angiogenesis and myocardial dysfunction following MI in the diabetic rat through PHD3 inhibition.
他汀类药物（HMG-CoA还原酶抑制剂）已知可改善糖尿病诱发的心血管疾病中的心脏功能。我们研究了他汀类药物改善心肌梗死（MI）后心脏功能的机制。辛伐他汀（S）在体外增加了人脐静脉内皮细胞（HUVEC）的管腔形成和迁移。我们研究了辛伐他汀对链脲佐菌素（STZ）诱导的糖尿病大鼠心肌梗死后心脏功能的作用。
将大鼠随机分为1）对照（非糖尿病）假手术组（CS）；2）对照（非糖尿病）心肌梗死组（CMI）；3）对照他汀治疗假手术组（CSS）；4）对照他汀治疗心肌梗死组（CSMI）；5）糖尿病假手术组（DS）；6）糖尿病心肌梗死组（DMI）；7）糖尿病他汀治疗假手术组（DSS）；8）糖尿病他汀治疗心肌梗死组（DSMI）。在注射STZ/生理盐水两周后，灌胃给予辛伐他汀（1mg/kg体重），持续15天（d）。在治疗30天后通过永久性结扎左冠状动脉前降支诱导心肌梗死。
辛伐他汀治疗的心肌梗死组在心肌梗死后30天时显示小动脉密度增加（23±0.6对14.8±0.4个/mm²，DSMI对DMI）且纤维化减少。心肌梗死后4天通过酶联免疫吸附测定（ELISA）测量血管内皮生长因子（VEGF）显示，与DMI组相比，DSMI组表达增加。蛋白质印迹分析显示，与DMI组相比，DSMI组脯氨酰-4-羟化酶3（PHD-3）减少。心肌梗死后4周的超声心动图分析显示，无论糖尿病状态如何，两个他汀治疗的心肌梗死组的射血分数（50.11±1.83对32.46±2.19%；DSMI对DMI）和缩短分数（26.77±1.12对16.36±1.22%；DSMI对DMI）均有显著改善。
这些结果表明，他汀治疗通过抑制PHD3减轻糖尿病大鼠心肌梗死后的血管生成受损和心肌功能障碍。
