PDF(Pubmed)
Abstract：
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 (CoCl2) to simulate low-oxygen conditions. We found that CoCl2 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.
摘要：
缺血性心脏病（IHD）仍然是全球主要的健康问题，缺血再灌注损伤加剧心肌损伤，尽管有治疗干预。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。使用AC16和H9c2细胞系，我们通过用氯化钴（CoCl2）处理细胞来模拟低氧条件，建立了化学缺氧模型。我们发现CoCl2处理显著上调心肌细胞缺氧诱导因子1α(HIF-1α)的表达,表明成功诱导缺氧。随后的形态学和生化分析显示，缺氧改变了心肌细胞的形态，破坏了细胞骨架。并造成细胞损伤，伴随乳酸脱氢酶（LDH）释放和丙二醛（MDA）水平增加，超氧化物歧化酶(SOD)活性降低,指示氧化应激。慢病毒介导的TPM3过表达减毒缺氧诱导的形态学变化，细胞损伤,和氧化应激失衡，而TPM3敲低加剧了这些影响。此外，HDAC1抑制剂MGCD0103治疗部分逆转了TPM3敲低引起的缺氧诱导损伤的加重。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,我们的发现强调了TPM3调制在缓解缺氧相关心脏损伤中的治疗潜力，为缺血性心脏病和其他缺氧相关心脏病的治疗提供了有希望的途径。
