Gene expression profiling in hypertrophied heart as the determinant of phenotype of heart failure

我们利用Dahl盐敏感的舒张性心力衰竭或收缩性心力衰竭大鼠，分析了高血压心脏的基因表达模式。利用基因芯片技术对不同心力衰竭表型的心脏组织进行了约8000个基因的表达谱分析。在高血压心力衰竭模型中，在左心室扩张之前，基质金属蛋白酶(MMPs)的基因表达和活性增加。血管紧张素转换酶(ACE)抑制MMPs的激活，防止左心室重构和功能障碍。基质金属蛋白酶可能触发左室重构。血管紧张素转换酶抑制直接抑制基质金属蛋白酶，从而预防高血压心脏的心力衰竭。我们还分析了血管紧张素II 1型受体阻滞剂(ARB)和血管紧张素转换酶抑制剂(ACED)对舒张性心力衰竭(DHF)大鼠胶原合成和降解的影响。他们的给药类似地抑制了心室纤维化。ACEI组I型胶原基因表达下降，但降幅小于ARB组。ARB和ACEI通过不同的机制抑制DHF的心肌纤维化。在DHF中，在晚期开始应用ARB时，与单独使用ACEI相比，在ACEI中加入ARB可以提供更多的好处。N-甲基乙醇胺(MEA)在不释放机械应激的情况下，可能通过抑制磷脂酶D(PLD)活性和调节纤维化途径，对心肌纤维化所致心脏疾病起到治疗作用。

We analyzed gene expression pattern in hypertensive heart using Dahl salt-sensitive rats with diastolic heart failure or systolic heart failure. Expression profiling of mRNA reveals several clusters in approximate 8000 genes using cDNA array method for heart tissue of those different phenotypes of heart failure.Enhancement of gene expression and activity of matrix metalloproteinases (MMPs ) preceded LV dilatation in a hypertensive heart failure model. Angiotensin converting enzyme (ACE) inhibition suppressed the preceding activation of MMPs and prevented LV remodeling and dysfunction. MMPs are likely to trigger LV remodeling. ACE inhibition directly inhibits MMPs, leading to prevention of heart failure in hypertensive heart. We also analyzed the effects of angiotensin II type 1 receptor Mocker (ARB) and angiotensin converting enzyme inhibitor (ACED on the synthesis and degradation of collagens in a rat model of diastolic heart failure (DHF). Their administration similarly inhibited ventricular fibrosis. The ACEI administration decreased type I collagen mRNA level, but the decrease was less than that induced by the ARB administration. ARB and ACEI inhibited ventricular fibrosis through different mechanisms in DHF. ARB added to ACEI provides more benefits as compared with ACEI alone in DHF when initiated at advanced stage. The additive effects are likely provided through more prominent suppression of ROS generation and inflammatory changes without effects on expression of MCP-1 and TNF-alpha.N-methylethanolamine (MEA) may exert therapeutic effects on cardiac disorders due to ventricular fibrosis through suppression of phospholipase D (PLD) activity and modulation of fibrosis pathway even without a release from mechanical stress.