Anthracycline-induced cardiomyopathies and sarcopenia are frequently seen in cancer patients, affecting their overall survival and quality of life; therefore, new cardioprotective and anti-sarcopenic strategies are needed. Vericiguat is a new oral guanylate cyclase activator that reduces heart failure hospitalizations or cardiovascular death. This study highlighted the potential cardioprotective and anti-sarcopenic properties of vericiguat during anthracycline therapy. Human cardiomyocytes and primary skeletal muscle cells were exposed to doxorubicin (DOXO) with or without a pre-treatment with vericiguat. Mitochondrial cell viability, LDH, and Cytochrome C release were performed to study cytoprotective properties. Intracellular Ca++content, TUNEL assay, cGMP, NLRP-3, Myd-88, and cytokine intracellular levels were quantified through colorimetric and selective ELISA methods. Vericiguat exerts significant cytoprotective and anti-apoptotic effects during exposure to doxorubicin. A drastic increase in cGMP expression and reduction in NLRP-3, MyD-88 levels were also seen in Vericiguat-DOXO groups vs. DOXO groups (p< 0.001) in both cardiomyocytes and human muscle cells. GCa vericiguat reduces cytokines and chemokines involved in heart failure and sarcopenia. The findings that emerged from this study could provide the rationale for further preclinical and clinical investigations aimed at reducing anthracycline cardiotoxicity and sarcopenia in cancer patients.
蒽环类药物诱发的心肌病与肌肉减少症在癌症患者中较为常见，显著影响患者总体生存率与生活质量，因此亟需开发新型心脏保护及抗肌肉减少策略。维利西呱作为一种新型口服鸟苷酸环化酶激活剂，可有效降低心力衰竭住院率及心血管死亡率。本研究重点探讨了蒽环类药物治疗期间维利西呱潜在的心脏保护与抗肌肉减少特性。实验将人心肌细胞与原代骨骼肌细胞分别暴露于多柔比星环境，部分细胞组预先接受维利西呱处理。通过检测线粒体细胞活性、乳酸脱氢酶及细胞色素C释放水平评估细胞保护特性，并采用比色法与选择性ELISA法量化细胞内钙离子浓度、TUNEL检测结果、环磷酸鸟苷、NLRP-3炎症小体、髓样分化因子88及细胞因子水平。研究显示，维利西呱在多柔比星暴露条件下能发挥显著的细胞保护与抗凋亡作用。与单纯多柔比星组相比，维利西呱-多柔比星联合处理组在心肌细胞与人类肌肉细胞中均呈现环磷酸鸟苷表达急剧升高，同时NLRP-3与髓样分化因子88水平显著降低（p<0.001）。维利西呱还能有效降低与心力衰竭及肌肉减少症相关的细胞因子与趋化因子水平。本研究结果为开展进一步临床前及临床研究提供了理论依据，有望为降低癌症患者蒽环类药物心脏毒性及肌肉减少症风险开辟新途径。
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