Cardiovascular Research Institute, Baylor College of Medicine, Houston, TX 77030, U.S.A.
Department of Integrative Physiology, Baylor College of Medicine, Houston, TX 77030, U.S.A.
Clin Sci (Lond). 2024 Sep 18;138(18):1173-1177. doi: 10.1042/CS20241421.
Cardiac functional, morphological, and histological analysis, coupled with liquid chromatography and mass spectrometry, of two transgenic mouse models with cardiomyocyte-specific overexpression of insulin-like growth factor 1 receptor (IGF1R) or a dominant-negative PI3K mutant (DCM-dnPI3K) revealed distinctive functional and molecular profiles during physiological (driven by IGF1R overexpression) and pathological (driven by dn-PI3K overexpression) atrial remodeling. The current study confirmed previously reported findings, including ventricular dilatation and enhanced systolic function with no evidence of arrhythmia in IGF1R model, as well as ventricular hypertrophy and decreased systolic function with intermittent atrial fibrillation in DCM-dnPI3K model. Novel findings obtained from the left atrial (LA) characterization of female mice revealed that physiological atrial enlargement resulted from increased atrial myocyte size and was associated with preserved atrial function, as determined by maintained LA ejection fraction (EF). The proteomic profile of IGF1R transgenic (Tg) mice was enriched for metabolic remodeling and showed a protein expression pattern similar to that of healthy human atria; on the other hand, pathological atrial enlargement resulted from increased atrial fibrosis with normal myocyte size and was associated with impaired atrial function due to a reduced LA EF. The proteomic profile of DCM-dnPI3K mice was enriched to both metabolic and structural remodeling and showed a protein expression pattern similar to that of human AF atria.
采用心脏功能、形态和组织学分析，结合液相色谱-质谱联用技术，对两种转基因小鼠模型（心肌细胞特异性过表达胰岛素样生长因子 1 受体（IGF1R）或显性负 PI3K 突变体（DCM-dnPI3K））进行分析，揭示了在生理（由 IGF1R 过表达驱动）和病理（由 dn-PI3K 过表达驱动）心房重构过程中独特的功能和分子特征。本研究证实了先前的研究结果，包括 IGF1R 模型中出现心室扩张和收缩功能增强而无心律失常的现象，以及 DCM-dnPI3K 模型中出现心室肥厚和收缩功能降低伴间歇性心房颤动的现象。从雌性小鼠左心房（LA）特征分析中获得的新发现表明，生理性心房扩张是由于心房肌细胞大小增加所致，与心房功能保持不变有关，LA 射血分数（EF）保持不变。IGF1R 转基因（Tg）小鼠的蛋白质组学特征富含代谢重塑，其蛋白表达模式与健康人类心房相似；另一方面，病理性心房扩张是由于心房纤维化增加而肌细胞大小正常所致，与 LA EF 降低导致心房功能受损有关。DCM-dnPI3K 小鼠的蛋白质组学特征富含代谢和结构重塑，其蛋白表达模式与人类房颤心房相似。
