Langa Paulina, Bacon Angelie, Warren Chad M, Chowdhury Shamim A K, Halas Monika, Fernandes Aurelia A, McCauley Mark D, Goldspink Paul H, Solaro R John, Wolska Beata M
Department of Physiology and Biophysics, College of Medicine, University of Illinois, Chicago, IL, United States.
Center for Cardiovascular Research, College of Medicine, University of Illinois, Chicago, IL, United States.
Front Physiol. 2025 May 23;16:1600117. doi: 10.3389/fphys.2025.1600117. eCollection 2025.
Hypertrophic cardiomyopathy (HCM) is a genetic disease caused by mutations in sarcomeric proteins. Mutations in sarcomeric proteins that give rise to cardiomyopathies produce abnormalities in the biophysical properties of the sarcomere that are propagated beyond the cardiac myocyte. In this study, we evaluated the hypothesis that early desensitization of myofilament Ca sensitivity in the TnT-R92Q mouse model, achieved through the introduction of pseudo-phosphorylated TnI (TnI-S23,24D or TnI-DD), may delay the progression of the HCM phenotype in cardiac myocyte and endothelial cellular compartments of the heart. We studied non-transgenic mice, transgenic (TG) mice expressing TnT-R92Q (TnT-R92Q), TG mice expressing TnI-DD, and double transgenic mice expressing TnT-R92Q and TnI-DD at 28 days and 16 weeks of age. Experiments reported here demonstrate that expression of TnI-DD in the TnT-R92Q HCM mouse model results in partial normalization of myofilament Ca sensitivity, improved cardiac morphology and function, reduced fibrosis, normalization of YAP signaling in endothelial cells, but a lack of normalization of coronary flow parameters. The novelty of the approach reported here highlights that although small corrections made to offset the sarcomeric defect may not fully or immediately resolve the disease's pathophysiologic state, they can lessen the severity of HCM. Our findings further support the concept that early desensitization of myofilaments to Ca in HCM, mainly when arising from mutations in thin filament proteins, represents a promising avenue for developing new therapeutic drugs.
肥厚型心肌病(HCM)是一种由肌节蛋白突变引起的遗传性疾病。导致心肌病的肌节蛋白突变会在肌节的生物物理特性中产生异常,这种异常会传播到心肌细胞之外。在本研究中,我们评估了这样一种假设:通过引入假磷酸化肌钙蛋白I(TnI-S23,24D或TnI-DD)在TnT-R92Q小鼠模型中实现肌丝钙敏感性的早期脱敏,可能会延缓心脏心肌细胞和内皮细胞区室中HCM表型的进展。我们研究了非转基因小鼠、表达TnT-R92Q的转基因(TG)小鼠、表达TnI-DD的TG小鼠以及在28天和16周龄时表达TnT-R92Q和TnI-DD的双转基因小鼠。此处报道的实验表明,在TnT-R92Q HCM小鼠模型中表达TnI-DD会导致肌丝钙敏感性部分恢复正常,改善心脏形态和功能,减少纤维化,使内皮细胞中的YAP信号正常化,但冠状动脉血流参数未恢复正常。此处报道的方法的新颖之处在于,尽管为抵消肌节缺陷所做的微小校正可能无法完全或立即解决疾病的病理生理状态,但它们可以减轻HCM的严重程度。我们的研究结果进一步支持了这样一种概念,即HCM中肌丝对钙的早期脱敏,主要是当由细肌丝蛋白突变引起时,代表了开发新治疗药物的一个有前景的途径。