Warren Chad M, Halas Monika, Feng Han-Zhong, Wolska Beata M, Jin Jian-Ping, Solaro R John
Department of Physiology & Biophysics, Center for Cardiovascular Research, University of Illinois at Chicago, USA.
Division of Cardiology, Center for Cardiovascular Research, University of Illinois at Chicago, USA.
J Cell Signal. 2021;2(3):162-171.
Cardiac sarcomeres express a variant of troponin I (cTnI) that contains a unique N-terminal extension of ~30 amino acids with regulatory phosphorylation sites. The extension is important in the control of myofilament response to Ca, which contributes to the neuro-humoral regulation of the dynamics of cardiac contraction and relaxation. Hearts of various species including humans express a stress-induced truncated variant of cardiac troponin I (cTnI-ND) missing the first ~30 amino acids and functionally mimicking the phosphorylated state of cTnI. Studies have demonstrated that upregulation of cTnI-ND potentially represents a homeostatic mechanism as well as an adaptive response in pathophysiology including ischemia/reperfusion injury, beta adrenergic maladaptive activation, and aging. We present evidence showing that cTnI-ND can modify the trigger for hypertrophic cardiomyopathy (HCM) by reducing the Ca sensitivity of myofilaments from hearts with an E180G mutation in α-tropomyosin. Induction of this truncation may represent a therapeutic approach to modifying Ca-responses in hearts with hypercontractility or heat failure with preserved ejection fraction.
心肌肌节表达一种肌钙蛋白I（cTnI）变体，其包含一个约30个氨基酸的独特N端延伸序列，带有调节性磷酸化位点。该延伸序列在控制肌丝对钙离子的反应中起重要作用，这有助于对心脏收缩和舒张动力学进行神经体液调节。包括人类在内的各种物种的心脏都表达一种应激诱导的心肌肌钙蛋白I截短变体（cTnI-ND），它缺失最初的约30个氨基酸，在功能上模拟cTnI的磷酸化状态。研究表明，cTnI-ND的上调可能代表一种稳态机制以及在包括缺血/再灌注损伤、β肾上腺素能适应不良激活和衰老在内的病理生理学中的适应性反应。我们提供的证据表明，cTnI-ND可以通过降低α-原肌球蛋白中存在E180G突变的心脏肌丝对钙离子的敏感性来改变肥厚型心肌病（HCM）的触发因素。诱导这种截短可能代表一种治疗方法，用于改变收缩性增强或射血分数保留的心力衰竭心脏中的钙离子反应。
