Maar Klaudia, Thatcher Jeffrey E, Karpov Egor, Rendeki Szilard, Gallyas Ferenc, Bock-Marquette Ildiko
Department of Biochemistry and Medical Chemistry, University of Pecs Medical School, 7624 Pecs, Hungary.
Department of Cardiovascular and Thoracic Surgery, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
Int J Mol Sci. 2025 Apr 26;26(9):4131. doi: 10.3390/ijms26094131.
Although a myocardial infarction occurs roughly every minute in the U.S. alone, medical research has yet to unlock the key to fully enabling post-hypoxic myocardial regeneration. Thymosin beta-4 (TB4), a short, secreted peptide, was shown to possess a beneficial impact regarding myocardial cell survival, coronary re-growth and progenitor cell activation following myocardial infarction in adult mammals. It equally reduces scarring, however, the precise mechanisms through which the peptide assists this phenomenon have not been properly elucidated. Accordingly, the primary aim of our study was to identify novel molecular contributors responsible for the positive impact of TB4 during the remodeling processes of the infarcted heart. We performed miRNA profiling on adult mice hearts following permanent coronary ligation with or without systemic TB4 injection and searched for targets and novel mechanisms through which TB4 may mitigate pathological scarring in the heart. Our results revealed a significant increase in miR139-5p expression and identified ROCK1 as a potential target protein aligned. Real-time PCR, Western blot and immunostaining on adult mouse hearts and human cardiac cells revealed the peptide indirectly or directly modulates ROCK1 protein levels both in vivo and in vitro. We equally discovered TB4 may reverse or inhibit fibroblast/myofibroblast transformation and the potential downstream mechanisms by which TB4 alters cellular responses through ROCK1 are cell type specific. Given the beneficial effects of ROCK1 inhibition in various cardiac pathologies, we propose a potential utilization for TB4 as a ROCK1 inhibitor in the future.
尽管仅在美国，心肌梗死大约每分钟就会发生一次，但医学研究尚未找到完全实现缺氧后心肌再生的关键。胸腺素β-4（TB4）是一种短小的分泌肽，在成年哺乳动物心肌梗死后，它对心肌细胞存活、冠状动脉再生长和祖细胞激活具有有益影响。它同样能减少瘢痕形成，然而，该肽促进这一现象的确切机制尚未得到充分阐明。因此，我们研究的主要目的是确定在梗死心脏重塑过程中对TB4的积极影响起作用的新分子。我们对成年小鼠心脏进行了永久性冠状动脉结扎，结扎前后分别进行全身TB4注射，然后进行miRNA分析，寻找TB4减轻心脏病理性瘢痕形成的靶点和新机制。我们的结果显示miR139-5p表达显著增加，并确定ROCK1为潜在的靶蛋白。对成年小鼠心脏和人类心脏细胞进行实时PCR、蛋白质印迹和免疫染色，结果显示该肽在体内和体外均可间接或直接调节ROCK1蛋白水平。我们还发现TB4可能逆转或抑制成纤维细胞/肌成纤维细胞转化，并且TB4通过ROCK1改变细胞反应的潜在下游机制具有细胞类型特异性。鉴于抑制ROCK1在各种心脏疾病中具有有益作用，我们提出未来TB4有可能作为ROCK1抑制剂加以应用。
