Pang Yanan, Wu Luyao, Xia Jiachun, Xu Xin, Gao Chenshan, Hou Lei, Jiang Li
Institute of Cardiovascular Diseases, Tongren Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200336, P.R. China.
Division of Cardiology, Tongren Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200336, P.R. China.
Int J Mol Med. 2025 Jun;55(6). doi: 10.3892/ijmm.2025.5539. Epub 2025 May 2.
Pathological cardiac hypertrophy is a major contributor to heart failure (HF), resulting in high mortality rates worldwide; therefore, identifying key molecules in pathological cardiac hypertrophy is of critical importance for preventing or reversing HF. Tripartite motif 38 (Trim38) is an E3 ubiquitin ligase that serves a pivotal role in various diseases. The present study aimed to elucidate the regulatory role of Trim38 in pressure overload‑induced pathological cardiac hypertrophy and to explore its underlying molecular mechanisms. The expression of Trim38 was decreased in hypertrophic heart tissues from a murine model of transverse aortic constriction (TAC) and in neonatal rat cardiomyocytes (NRCMs) treated with phenylephrine (PE). Furthermore, Trim38 knockout (Trim38‑KO) aggravated cardiac hypertrophy after TAC, and Trim38 knockdown in cardiomyocytes increased cell cross section area, and upregulated the expression of atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP) following treatment with PE. Ubiquitinomics analysis revealed that the MAPK signaling pathway was regulated by Trim38. Furthermore, western blotting confirmed that Trim38‑KO activated TAK1 and JNK/P38. By contrast, Trim38 overexpression in NRCMs suppressed the JNK/P38 signaling pathway and inhibited the phosphorylation of TAK1. Furthermore, Trim38 knockdown resulted in a marked enhancement of TAK1 phosphorylation, concomitant with an augmentation of cardiomyocyte area and a significant upregulation of the hypertrophic biomarkers ANP and BNP. By contrast, infection with an adenovirus containing dominant‑negative TAK1 inhibited TAK1 activity, which attenuated Trim38 knockdown‑induced cardiomyocyte hypertrophy, confirming that TAK1 is a key molecule involved in the protective effects of Trim38 on cardiomyocytes. In conclusion, to the best of our knowledge, the present study is the first to reveal that Trim38 confers protection against pathological cardiac hypertrophy by inhibiting the TAK1/JNK/P38 signaling pathway; therefore, Trim38 may be a promising target for treating cardiac hypertrophy.
病理性心脏肥大是导致心力衰竭（HF）的主要因素，在全球范围内造成了较高的死亡率；因此，确定病理性心脏肥大中的关键分子对于预防或逆转HF至关重要。三联基序38（Trim38）是一种E3泛素连接酶，在多种疾病中起关键作用。本研究旨在阐明Trim38在压力超负荷诱导的病理性心脏肥大中的调节作用，并探讨其潜在的分子机制。在横向主动脉缩窄（TAC）小鼠模型的肥厚心脏组织以及用去甲肾上腺素（PE）处理的新生大鼠心肌细胞（NRCMs）中，Trim38的表达降低。此外，Trim38基因敲除（Trim38-KO）加重了TAC后的心脏肥大，心肌细胞中Trim38的敲低增加了细胞横截面积，并在PE处理后上调了心钠素（ANP）和脑钠肽（BNP）的表达。泛素组学分析显示，丝裂原活化蛋白激酶（MAPK）信号通路受Trim38调控。此外，蛋白质免疫印迹法证实Trim38-KO激活了转化生长因子-β激活激酶1（TAK1）和c-Jun氨基末端激酶/ P38（JNK/P38）。相比之下，NRCMs中Trim38的过表达抑制了JNK/P38信号通路，并抑制了TAK1的磷酸化。此外，Trim38的敲低导致TAK1磷酸化显著增强，同时心肌细胞面积增大，肥厚生物标志物ANP和BNP显著上调。相比之下，感染含有显性负性TAK1的腺病毒可抑制TAK1活性，从而减轻Trim38敲低诱导的心肌细胞肥大，证实TAK1是Trim38对心肌细胞保护作用的关键分子。总之，据我们所知，本研究首次揭示Trim38通过抑制TAK1/JNK/P38信号通路对病理性心脏肥大具有保护作用；因此，Trim38可能是治疗心脏肥大的一个有前景的靶点。
