Zhang Pengfei, Deng Huifang, Lan Xiong, Shen Pan, Bai Zhijie, Huangfu Chaoji, Wang Ningning, Xiao Chengrong, Gao Yehui, Sun Yue, Li Jiamiao, Guo Jie, Zhou Wei, Gao Yue
Beijing Institute of Radiation Medicine, Beijing 100850, China.
State Key Laboratory of Kidney Diseases, Chinese PLA General Hospital, Beijing 100853, China.
Int J Mol Sci. 2024 Dec 24;26(1):54. doi: 10.3390/ijms26010054.
Chronic exposure to high altitudes causes pathophysiological cardiac changes that are characterized by cardiac dysfunction, cardiac hypertrophy, and decreased energy reserves. However, finding specific pharmacological interventions for these pathophysiological changes is challenging. In this study, we identified tetramethylpyrazine (TMP) as a promising drug candidate for cardiac dysfunction caused by simulated high-altitude exposure. By utilizing hypobaric chambers to simulate high-altitude environments, we found that TMP improved cardiac function, alleviated cardiac hypertrophy, and reduced myocardial injury in hypobaric hypoxic mice. RNA sequencing showed that TMP also upregulated heart-contraction-related genes that were suppressed by hypobaric hypoxia exposure. Mechanistically, TMP inhibited hypobaric hypoxia-induced cardiac Ca/calmodulin-dependent kinase II (CaMKII) activation and exerted cardioprotective effects by inhibiting CaMKII. Our data suggest that TMP application may be a promising approach for treating high-altitude-induced cardiac dysfunction, and they highlight the crucial role of CaMKII in hypobaric hypoxia-induced cardiac pathophysiology.
长期暴露于高海拔地区会导致病理生理性心脏变化，其特征为心脏功能障碍、心脏肥大和能量储备减少。然而，找到针对这些病理生理变化的特定药物干预措施具有挑战性。在本研究中，我们确定川芎嗪（TMP）是一种有前景的治疗模拟高海拔暴露所致心脏功能障碍的候选药物。通过利用低压舱模拟高海拔环境，我们发现TMP改善了低压低氧小鼠的心脏功能，减轻了心脏肥大，并减少了心肌损伤。RNA测序表明，TMP还上调了因低压低氧暴露而被抑制的心脏收缩相关基因。从机制上讲，TMP抑制了低压低氧诱导的心脏钙/钙调蛋白依赖性激酶II（CaMKII）激活，并通过抑制CaMKII发挥心脏保护作用。我们的数据表明，应用TMP可能是治疗高海拔诱导的心脏功能障碍的一种有前景的方法，并且它们突出了CaMKII在低压低氧诱导的心脏病理生理学中的关键作用。
