Pathophysiological role and mechanism of apoptosis in human congestive heart hailure

Fas和Fas配体(Fas-L)是细胞表面蛋白，具有代表性的细胞凋亡信号分子。当细胞膜上的Fas与Fas-L或sFas-L结合时，细胞膜上的Fas可诱导细胞凋亡。而缺乏Fas跨膜区的分子血浆SEA通过抑制Fas-L与细胞膜上Fas-L的结合而阻断细胞凋亡。根据结节性心力衰竭(CHF)患者NYHA分级，我们发现血浆可溶性FAR(SEA)水平升高。由于细胞凋亡在CHE的进展中起重要作用，而sFas是细胞凋亡的抑制因子，我们推测在NYHA IV型重度充血性心力衰竭患者中，高sFas水平患者的预后好于sFas水平正常的患者。sFas水平高的患者6个月和1年存活率分别为68%和%，而正常sFas组的6个月和1年存活率分别为68%和11%(正常者高于3.7 ng/mL，平均±2SD)。重度CHF患者的预后在高SFAS组明显好于正常SFAS组(p&lt；0.01)。此外，我们报道了1)TUNEL阳性和DNA梯状条带的梗死区所谓的凋亡心肌细胞是超微结构的肿瘤性(坏死性)心肌细胞，DNA片段化2)心肌梗死后间质细胞消失是由于细胞凋亡3)DCM中所有TUNEL阳性的心肌细胞同时表达增殖或修复指标PCNA，但不表达复制指标Ki 67。超微结构不是凋亡或坏死，而是有核的活细胞。也就是说，DCM心脏组织中TUNEL阳性的心肌细胞不是凋亡细胞，而是DNA修复活性增强的活细胞。

Fas and Fas ligand (Fas-L) are cell-surface proteins and representative apoptosis-signaling molecules. Fas on the cell membrane induces apoptosis when it binds Fas-L or sFas-L.However, plasma sEas, a molecule lacking the transmembrane domain of Fas, blockes apoptosis by inhibiting binding between Far and Fas-L on the cell membrane. We found elevated levels of plasma soluble Far (sEas), according to the grade of NYHA in the patient with conjestive heart failure (CHF). But an increase in plasma sFas-ligand was not observed.As apoptosis plays an important role on the progression of CHE and sFas is an inhibitor of apoptosis, we postulated that the patients with high plasma sFas have better progrnosis than those with normal plasma sFas in severe congestive heart failure of NYHA IV.Survival rates for 6 months and 1 year were 68% and 64% in a high sPas group (over 3.7ng/mL, mean+2SD of normal subjects), and 1.4% and 11% in a normal sFas group (below 3.7ng/mL), respectively. The prognosis of severe CHF patients was definitely better in the high sFas group than in the normal sFas group (p<0.01).In addition, we reported that 1) so-called apoptotic myocytes in the infarct area presenting positive TUNEL and DNA ladder are ultrastructurally oncotic (necrotic) myocytes with DNA fragmentation 2) disappearance of interstitial cells after myocardial infarction is due to apoptosis 3) all of TUNEL-positive myocytes in DCM simultaneously expressed PCNA, an indicator of replication or repair, but did not express Ki 67, an indicator of replication. The ultrastructure was not apoptosis or necrosis, but that of living cell with nuclei. That is, TUNEL positive myocytes in hearts with DCM are not apoptotic, but living cells with increasing activity of DNA repair.