Shikama Yosuke, Otsuka Kunihiro, Shikama Yuka, Furukawa Masae, Ishimaru Naozumi, Matsushita Kenji
Department of Oral Disease Research, National Center for Geriatrics and Gerontology, Obu, Japan.
Department of Geriatric Oral Science, Graduate School of Dentistry, Tohoku University, Sendai, Japan.
Biofactors. 2025 Jan-Feb;51(1):e2154. doi: 10.1002/biof.2154.
SARS-CoV-2-related proteins, ACE2 and TMPRSS2, are determinants of SARS-CoV-2 infection. Although these proteins are expressed in oral-related tissues, their expression patterns and modulatory mechanisms in the salivary glands remain unknown. We herein showed that full-length ACE2, which has both a fully functional enzyme catalytic site and high-affinity SARS-CoV-2 spike S1-binding sites, was more highly expressed in salivary glands than in oral mucosal epithelial cells and the lungs. Regarding TMPRSS2, zymogen and the cleaved form were both expressed in the salivary glands, whereas only zymogen was expressed in murine lacrimal glands and the lungs. Metformin, an AMPK activator, increased stimulated saliva secretion and full-length ACE2 expression and decreased cleaved TMPRSS2 expression in the salivary glands, and exerted the same effects on soluble ACE2 (sACE2) and sTMPRSS2 in saliva. Moreover, metformin decreased the expression of beta-galactosidase, a senescence marker, and ADAM17, a sheddase of ACE2 to sACE2, in the salivary glands. In aged mice, the expression of ACE2 was decreased in the salivary glands, whereas that of sACE2 was increased in saliva, presumably by the up-regulated expression of ADAM17. The expression of TMPRSS2 in the salivary glands and sTMPRSS2 in saliva were both increased. Collectively, these results suggest that the protein expression patterns of ACE2 and TMPRSS2 in the salivary glands differ from those in other oral-related cells and tissues, and also that metformin and aging affect the salivary expression of ACE2 and TMPRSS2, which have the potential as targets for preventing the transmission of SARS-CoV-2.
与严重急性呼吸综合征冠状病毒2（SARS-CoV-2）相关的蛋白，即血管紧张素转换酶2（ACE2）和跨膜丝氨酸蛋白酶2（TMPRSS2），是SARS-CoV-2感染的决定因素。尽管这些蛋白在口腔相关组织中表达，但其在唾液腺中的表达模式和调节机制仍不清楚。我们在此表明，具有完整功能的酶催化位点和高亲和力SARS-CoV-2刺突S1结合位点的全长ACE2在唾液腺中的表达高于口腔黏膜上皮细胞和肺。关于TMPRSS2，酶原和裂解形式在唾液腺中均有表达，而在小鼠泪腺和肺中仅表达酶原。二甲双胍，一种AMPK激活剂，可增加刺激后的唾液分泌和全长ACE2表达，并降低唾液腺中裂解的TMPRSS2表达，对唾液中的可溶性ACE2（sACE2）和sTMPRSS2也有相同作用。此外，二甲双胍降低了唾液腺中衰老标志物β-半乳糖苷酶以及将ACE2裂解为sACE2的去整合素和金属蛋白酶17（ADAM17）的表达。在老年小鼠中，唾液腺中ACE2的表达降低，而唾液中sACE2的表达增加，这可能是由于ADAM17表达上调所致。唾液腺中TMPRSS2的表达以及唾液中sTMPRSS2的表达均增加。总的来说，这些结果表明，ACE2和TMPRSS2在唾液腺中的蛋白表达模式不同于其他口腔相关细胞和组织，而且二甲双胍和衰老会影响唾液中ACE2和TMPRSS2的表达，它们有可能成为预防SARS-CoV-2传播的靶点。
