College of Pharmacy and Natural Medicine Research Institute, Mokpo National University, Jeonnam, Republic of Korea.
Department of Life Science, Dongguk University-Seoul, 32 Dongguk-ro, Ilsandong-gu, Goyang-si, Gyeonggi-do 10326, Republic of Korea.
Biochem Pharmacol. 2023 Jun;212:115530. doi: 10.1016/j.bcp.2023.115530. Epub 2023 Apr 6.
Calcific aortic valve stenosis (CAVS), the third most prevalent cardiovascular disorder is known to impose a huge social and economic burden on patients. However, no pharmacotherapy has yet been established. Aortic valve replacement is the only treatment option, although its lifelong efficacy is not guaranteed and involves inevitable complications. So, there is a crucial need to find novel pharmacological targets to delay or prevent CAVS progression. Capsaicin is well known for its anti-inflammatory and antioxidant properties and has recently been revealed to inhibit arterial calcification. We thus investigated the effect of capsaicin in attenuating aortic valve interstitial cells (VICs) calcification induced by pro-calcifying medium (PCM). Capsaicin reduced the level of calcium deposition in calcified VICs, along with reductions in gene and protein expression of the calcification markers Runx2, osteopontin, and BMP2. Based on Gene Ontology biological process and Kyoto Encyclopedia of Genes and Genomes pathway analysis oxidative stress, AKT and AGE-RAGE signaling pathways were selected. The AGE-RAGE signaling pathway activates oxidative stress and inflammation-mediated pathways including ERK and NFκB signaling pathways. Capsaicin successfully inhibited oxidative stress- and reactive oxygen species-related markers NOX2 and p22. The markers of the AKT, ERK1/2, and NFκB signaling pathways, namely, phosphorylated AKT, ERK1/2, NFκB, and IκBα were upregulated in calcified cells, while being significantly downregulated upon capsaicin treatment. Capsaicin attenuates VICs calcification in vitro by inhibition of redox-sensitive NFκB/AKT/ERK1/2 signaling pathway, indicating its potential as a candidate to alleviate CAVS.
钙化性主动脉瓣狭窄（CAVS）是第三大常见心血管疾病，已知会给患者带来巨大的社会和经济负担。然而，目前尚未确立任何药物治疗方法。主动脉瓣置换是唯一的治疗选择，尽管其终身疗效无法保证，并且涉及不可避免的并发症。因此，迫切需要寻找新的药理学靶点来延缓或预防 CAVS 进展。辣椒素以其抗炎和抗氧化特性而闻名，最近已被证实可抑制动脉钙化。因此，我们研究了辣椒素在减轻促钙化介质（PCM）诱导的主动脉瓣膜间质细胞（VIC）钙化中的作用。辣椒素降低了钙化 VIC 中的钙沉积水平，同时降低了钙化标志物 Runx2、骨桥蛋白和 BMP2 的基因和蛋白表达。基于基因本体论生物过程和京都基因与基因组百科全书通路分析，选择了氧化应激、AKT 和 AGE-RAGE 信号通路。AGE-RAGE 信号通路激活氧化应激和炎症介导的途径，包括 ERK 和 NFκB 信号通路。辣椒素成功抑制了与氧化应激和活性氧相关的标志物 NOX2 和 p22。AKT、ERK1/2 和 NFκB 信号通路的标志物，即磷酸化 AKT、ERK1/2、NFκB 和 IκBα，在钙化细胞中上调，而在用辣椒素处理后显著下调。辣椒素通过抑制氧化还原敏感的 NFκB/AKT/ERK1/2 信号通路抑制 VICs 的体外钙化，表明其有潜力成为缓解 CAVS 的候选药物。
