Department of Internal Medicine III (Cardiology and Angiology), Innsbruck Medical University, Innsbruck, Austria.
Institute of Molecular Biotechnology of the Austrian Academy of Sciences (IMBA), Vienna, Austria.
Sci Rep. 2024 Sep 30;14(1):22661. doi: 10.1038/s41598-024-72783-4.
Unlike adult mammals, the hearts of neonatal mice possess the ability to completely regenerate from myocardial infarction (MI). This observation has sparked vast interest in deciphering the potentially lifesaving and morbidity-reducing mechanisms involved in neonatal cardiac regeneration. In mice, the regenerative potential is lost within the first week of life and coincides with a reduction of Insulin-like growth factor 1 receptor (Igf1r) expression in the heart. Igf1r is a well-known regulator of cardiomyocyte maturation and proliferation in neonatal mice. To test the role of Igf1r as a pivotal factor in cardiac regeneration, we knocked down (KD) Igf1r specifically in cardiomyocytes using recombinant adeno-associated virus (rAAV) delivery and troponin T promotor driven shRNAmirs. Cardiomyocyte specific Igf1r KD versus control mice were subjected to experimental MI by permanent ligation of the left anterior descending artery (LAD). Cardiac functional and morphological data were analyzed over a 21-day period. Neonatal Igf1r KD mice showed reduced systolic cardiac function and increased fibrotic cardiac remodeling 21 days post injury. This cardiac phenotype was associated with reduced cardiomyocyte nuclei mitosis and decreased AKT and ERK phosphorylation in Igf1r KD, compared to control neonatal mouse hearts. Our in vivo murine data show that Igf1r KD shifts neonatal cardiac regeneration to a more adult-like scarring phenotype, identifying cardiomyocyte-specific Igf1r signaling as a crucial component of neonatal cardiac regeneration.
与成年哺乳动物不同，新生小鼠的心脏具有从心肌梗死（MI）完全再生的能力。这一观察结果激发了人们极大的兴趣，去破译涉及新生心脏再生的潜在救生和降低发病率的机制。在小鼠中，再生潜力在生命的第一周内丧失，并且与心脏中胰岛素样生长因子 1 受体（Igf1r）表达的减少同时发生。Igf1r 是调节新生小鼠心肌细胞成熟和增殖的众所周知的调节剂。为了测试 Igf1r 作为心脏再生关键因素的作用，我们使用重组腺相关病毒（rAAV）递送和肌钙蛋白 T 启动子驱动 shRNAmirs 在心肌细胞中特异性敲低（KD）Igf1r。心肌细胞特异性 Igf1r KD 与对照小鼠通过永久性结扎左前降支（LAD）接受实验性 MI。在 21 天的时间内分析心脏功能和形态数据。新生 Igf1r KD 小鼠在损伤后 21 天表现出收缩性心脏功能降低和纤维化心脏重构增加。与对照新生小鼠心脏相比，这种心脏表型与 Igf1r KD 中的心肌细胞核有丝分裂减少以及 AKT 和 ERK 磷酸化减少有关。我们的体内小鼠数据表明，Igf1r KD 将新生心脏再生转变为更类似于成人的瘢痕形成表型，确定心肌细胞特异性 Igf1r 信号作为新生心脏再生的关键组成部分。
