Bennett Mosi K, Sweet Wendy E, Baicker-McKee Sara, Looney Elizabeth, Karohl Kristen, Mountis Maria, Tang W H Wilson, Starling Randall C, Moravec Christine S
From the Kaufman Center for Heart Failure, Department of Cardiovascular Medicine, Cleveland Clinic, OH.
Circ Heart Fail. 2014 Jul;7(4):612-8. doi: 10.1161/CIRCHEARTFAILURE.113.000849. Epub 2014 May 19.
We hypothesized that S100A1 is regulated during human hypertrophy and heart failure and that it may be implicated in remodeling after left ventricular assist device. S100A1 is decreased in animal and human heart failure, and restoration produces functional recovery in animal models and in failing human myocytes. With the potential for gene therapy, it is important to carefully explore human cardiac S100A1 regulation and its role in remodeling.
We measured S100A1, the sarcoplasmic endoplasmic reticulum Ca(2+)ATPase, phospholamban, and ryanodine receptor proteins, as well as β-adrenergic receptor density in nonfailing, hypertrophied (left ventricular hypertrophy), failing, and failing left ventricular assist device-supported hearts. We determined functional consequences of protein alterations in isolated contracting muscles from the same hearts. S100A1, sarcoplasmic endoplasmic reticulum Ca(2+)ATPase and phospholamban were normal in left ventricular hypertrophy, but decreased in failing hearts, while ryanodine receptor was unchanged in either group. Baseline muscle contraction was not altered in left ventricular hypertrophy or failing hearts. β-Adrenergic receptor and inotropic response were decreased in failing hearts. In failing left ventricular assist device-supported hearts, S100A1 and sarcoplasmic endoplasmic reticulum Ca(2+)ATPase showed no recovery, while phospholamban, β-adrenergic receptor, and the inotropic response fully recovered.
S100A1 and sarcoplasmic endoplasmic reticulum Ca(2+)ATPase, both key Ca(2+)-regulatory proteins, are decreased in human heart failure, and these changes are not reversed after left ventricular assist device. The clinical significance of these findings for cardiac recovery remains to be addressed.
我们推测，S100A1在人类心肌肥厚和心力衰竭过程中受到调控，并且可能与左心室辅助装置植入后的心脏重塑有关。在动物和人类心力衰竭中，S100A1水平降低，而恢复其水平可使动物模型和衰竭的人类心肌细胞功能恢复。鉴于基因治疗的可能性，仔细探究人类心脏中S100A1的调控及其在重塑中的作用非常重要。
我们检测了非衰竭、肥厚（左心室肥厚）、衰竭以及接受左心室辅助装置支持的衰竭心脏中S100A1、肌浆网Ca(2+)ATP酶、受磷蛋白和兰尼碱受体蛋白，以及β-肾上腺素能受体密度。我们还确定了来自同一心脏的离体收缩肌肉中蛋白质改变的功能后果。左心室肥厚时，S100A1、肌浆网Ca(2+)ATP酶和受磷蛋白水平正常，但在衰竭心脏中降低，而两组中的兰尼碱受体均未改变。左心室肥厚或衰竭心脏的基线肌肉收缩未改变。衰竭心脏中的β-肾上腺素能受体和变力反应降低。在接受左心室辅助装置支持的衰竭心脏中，S100A1和肌浆网Ca(2+)ATP酶未恢复，而受磷蛋白、β-肾上腺素能受体和变力反应完全恢复。
S100A1和肌浆网Ca(2+)ATP酶这两种关键的Ca(2+)调节蛋白在人类心力衰竭中降低，且这些变化在左心室辅助装置植入后并未逆转。这些发现对心脏恢复的临床意义仍有待探讨。
