{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,21]],"date-time":"2026-09-21T10:24:22Z","timestamp":1789986262243,"version":"4.0.1"},"reference-count":44,"publisher":"Wiley","issue":"1","license":[{"start":{"date-parts":[[2022,9,26]],"date-time":"2022-09-26T00:00:00Z","timestamp":1664150400000},"content-version":"vor","delay-in-days":268,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["81874403"],"award-info":[{"award-number":["81874403"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Oxidative Medicine and Cellular Longevity"],"published-print":{"date-parts":[[2022,1]]},"abstract":"<jats:p>Population aging has led to increased sick sinus syndrome (SSS) incidence; however, no effective and safe medical therapy has been reported thus far. Yixin\u2010Fumai granules (YXFMs), a Chinese medicine granule designed for bradyarrhythmia treatment, can effectively increase SSS patients\u2019 heart rate. Senescence\u2010induced sinoatrial node (SAN) degeneration is an important part of SSS pathogenesis, and older people often show high levels of oxidative stress; reactive oxygen species (ROS) accumulation in the SAN causes abnormal SAN pacing or conduction functions. The current study observed the protective effects of YXFMs on senescent SAN and explored the relationship between the NRF\u20102\/HO\u20101 pathway, SHOX2, and T\u2010type calcium channels. We selected naturally senescent C57BL\/6 mice with bradycardia to simulate SSS; electrocardiography, Masson\u2019s trichrome staining, and DHE staining were used to assess SAN function and tissue damage. Immunofluorescence staining and Western blotting were used to assay related proteins. <jats:italic>In vitro<\/jats:italic>, we treated human\u2010induced pluripotent stem cell\u2010derived atrial myocytes (hiPSC\u2010AMs) and mouse atrial myocyte\u2010derived cell line HL\u20101 with D\u2010galactose to simulate senescent SAN\u2010pacemaker cells. CardioExcyte96 was used to evaluate the pulsatile function of the hiPSC\u2010AMs, and the mechanism was verified by DCFH\u2010DA, immunofluorescence staining, RT\u2010qPCR, and Western blotting. The results demonstrated that YXFMs effectively inhibited senescence\u2010induced SAN hypofunction, and this effect possibly originated from scavenging of ROS and promotion of NRF\u20102, SHOX2, and T\u2010type calcium channel expression. <jats:italic>In vitro<\/jats:italic> experiment results indicated that ML385, si\u2010<jats:italic>SHOX2<\/jats:italic>, LDN193189, and Mibefradil reversed YXFMs\u2019 effects. Moreover, we, for the first time, found that ROS accumulation may hinder SHOX2 expression; YXFMs can activate SHOX2 through the NRF\u20102\/HO\u20101 pathway\u2010mediated ROS scavenging and then regulate CACNA1G through the SHOX2\/BMP4\/GATA4\/NKX2\u20105 axis, improve T\u2010type calcium channel function, and ameliorate the SAN dysfunction. Finally, through network pharmacology and molecular docking, we screened for the most stable YXFMs compound that docks to NRF\u20102, laying the foundation for future studies.<\/jats:p>","DOI":"10.1155\/2022\/8488269","type":"journal-article","created":{"date-parts":[[2022,9,26]],"date-time":"2022-09-26T22:50:38Z","timestamp":1664232638000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":11,"title":["NRF\u20102\/HO\u20101 Pathway\u2010Mediated SHOX2 Activation Is a Key Switch for Heart Rate Acceleration by Yixin\u2010Fumai 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