Myosin heavy chain gene expression in human heart failure
Myosin heavy chain gene expression in human heart failure
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DOI：
10.1172/jci119776
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发表时间：
1997-11-01
影响因子：
15.9
通讯作者：
Leinwand, LA
中科院分区：
文献类型：
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作者：
Nakao, K;Minobe, W;Leinwand, LA
肌球蛋白重链（myosin heavy chain，MyHC）α和β两种亚型存在于哺乳动物心室肌中，其相对表达与心肌收缩速度相关。几种病理刺激可以导致啮齿动物心室的MyHC组成从α-MyHC转变为β-MyHC。考虑到心脏MyHC亚型转变的潜在生理后果，我们确定了心肌收缩力显著受损的人心力衰竭中MyHC基因的表达。在这项研究中，我们定量了14名心脏供体候选人的左心室游离壁（LV）中α-和β-MyHC mRNA的相对量，这些心脏供体候选人没有心血管疾病或结构性心血管异常的病史。该组包括7例非衰竭（NF）心脏患者和7例表现出供体心脏功能障碍（DHD）的心脏患者。与19例因慢性终末期心力衰竭接受心脏移植的患者（F）进行比较。α-MyHC mRNA相对于总的量（即，NF-和DHD-LV中MyHC mRNA的表达与先前的报道相比高得惊人（分别为33.3+/-18.9和35.4+/-16.5%），并且显著高于F-LV中的水平，与心力衰竭的原因无关（2.2+/-3.5%，P < 0.0001）。NF-和DHD-LV的比值无显著差异。我们的研究结果表明，相当数量的α-MyHC mRNA在正常心脏中表达，并在慢性终末期心力衰竭中显著降低。如果蛋白质和酶活性与mRNA表达相关，这种分子改变可能足以解释F-LV的收缩功能障碍，并且针对增加α-MyHC基因表达的治疗可能是可行的。
Two isoforms of myosin heavy chain (MyHC), alpha and beta, exist in the mammalian ventricular myocardium, and their relative expression is correlated with the contractile velocity of cardiac muscle. Several pathologic stimuli can cause a shift in the MyHC composition of the rodent ventricle from alpha- to beta-MyHC. Given the potential physiological consequences of cardiac MyHC isoform shifts, we determined MyHC gene expression in human heart failure where cardiac contractility is impaired significantly. In this study, we quantitated the relative amounts of alpha- and beta-MyHC mRNA in the left ventricular free walls (LVs) of 14 heart donor candidates with no history of cardiovascular disease or structural cardiovascular abnormalities. This group consisted of seven patients with nonfailing (NF) hearts and seven patients with hearts that exhibited donor heart dysfunction (DHD). These were compared with 19 patients undergoing cardiac transplantation for chronic end-stage heart failure (F). The relative amounts of alpha-MyHC mRNA to total (i.e., alpha + beta) MyHC mRNA in the NF- and DHD-LVs were surprisingly high compared with previous reports (33.3+/-18.9 and 35.4+/-16.5%, respectively), and were significantly higher than those in the F-LVs, regardless of the cause of heart failure (2.2+/-3.5%, P < 0.0001). There was no significant difference in the ratios in NF-and DHD-LVs. Our results demonstrate that a considerable amount of alpha-MyHC mRNA is expressed in the normal heart, and is decreased significantly in chronic end-stage heart failure. If protein and enzymatic activity correlate with mRNA expression, this molecular alteration may be sufficient to explain systolic dysfunction in F-LVs, and therapeutics oriented towards increasing alpha-MyHC gene expression may be feasible.