Key Laboratory of Preclinical Study for New Drugs of Gansu Province, School of Basic Medical Sciences, Lanzhou University, Lanzhou 730030, China.
Key Laboratory of Dental Maxillofacial Reconstruction and Biological Intelligence Manufacturing, School of Stomatology, Lanzhou University, Lanzhou 730030, China.
Int J Mol Sci. 2024 Jun 20;25(12):6797. doi: 10.3390/ijms25126797.
Ischemic heart disease (IHD) remains a major global health concern, with ischemia-reperfusion injury exacerbating myocardial damage despite therapeutic interventions. In this study, we investigated the role of tropomyosin 3 (TPM3) in protecting cardiomyocytes against hypoxia-induced injury and oxidative stress. Using the AC16 and H9c2 cell lines, we established a chemical hypoxia model by treating cells with cobalt chloride (CoCl) to simulate low-oxygen conditions. We found that CoCl treatment significantly upregulated the expression of hypoxia-inducible factor 1 alpha (HIF-1α) in cardiomyocytes, indicating the successful induction of hypoxia. Subsequent morphological and biochemical analyses revealed that hypoxia altered cardiomyocyte morphology disrupted the cytoskeleton, and caused cellular damage, accompanied by increased lactate dehydrogenase (LDH) release and malondialdehyde (MDA) levels, and decreased superoxide dismutase (SOD) activity, indicative of oxidative stress. Lentivirus-mediated TPM3 overexpression attenuated hypoxia-induced morphological changes, cellular damage, and oxidative stress imbalance, while TPM3 knockdown exacerbated these effects. Furthermore, treatment with the HDAC1 inhibitor MGCD0103 partially reversed the exacerbation of hypoxia-induced injury caused by TPM3 knockdown. Protein-protein interaction (PPI) network and functional enrichment analysis suggested that TPM3 may modulate cardiac muscle development, contraction, and adrenergic signaling pathways. In conclusion, our findings highlight the therapeutic potential of TPM3 modulation in mitigating hypoxia-associated cardiac injury, suggesting a promising avenue for the treatment of ischemic heart disease and other hypoxia-related cardiac pathologies.
缺血性心脏病（IHD）仍然是一个主要的全球健康问题，尽管有治疗干预措施，但缺血再灌注损伤会加剧心肌损伤。在这项研究中，我们研究了原肌球蛋白 3（TPM3）在保护心肌细胞免受缺氧诱导的损伤和氧化应激中的作用。我们使用 AC16 和 H9c2 细胞系，通过用氯化钴（CoCl）处理细胞来模拟低氧条件，建立了化学缺氧模型。我们发现 CoCl 处理显著上调了心肌细胞中缺氧诱导因子 1α（HIF-1α）的表达，表明成功诱导了缺氧。随后的形态学和生化分析表明，缺氧改变了心肌细胞的形态，破坏了细胞骨架，并导致细胞损伤，伴随着乳酸脱氢酶（LDH）释放和丙二醛（MDA）水平增加，以及超氧化物歧化酶（SOD）活性降低，表明存在氧化应激。慢病毒介导的 TPM3 过表达减轻了缺氧诱导的形态变化、细胞损伤和氧化应激失衡，而 TPM3 敲低则加剧了这些效应。此外，用 HDAC1 抑制剂 MGCD0103 处理部分逆转了 TPM3 敲低引起的缺氧诱导损伤的加剧。蛋白质-蛋白质相互作用（PPI）网络和功能富集分析表明，TPM3 可能调节心肌发育、收缩和肾上腺素能信号通路。总之，我们的研究结果表明，调节 TPM3 在减轻与缺氧相关的心脏损伤方面具有治疗潜力，为治疗缺血性心脏病和其他与缺氧相关的心脏病变提供了有前途的途径。
