Pilocarpine mediated excessive calcium accumulation leads to ciliary muscle cell senescence and apoptosis

作者全名："Gao, Xiang; Gao, Ning; Du, Miaomiao; Xiang, Yongguo; Zuo, Hangjia; Cao, Huijie; Zheng, Shijie; Huang, Rongxi; Wan, Wenjuan; Hu, Ke"

作者地址："[Gao, Xiang; Gao, Ning; Du, Miaomiao; Xiang, Yongguo; Zuo, Hangjia; Cao, Huijie; Zheng, Shijie; Wan, Wenjuan; Hu, Ke] Chongqing Med Univ, Chongqing Eye Inst, Chongqing Key Lab Prevent & Treatment Major Blindi, Affiliated Hosp 1,Chongqing Branch,Municipal Div,N, Chongqing 400016, Peoples R China; [Huang, Rongxi] Chongqing Gen Hosp, Chongqing, Peoples R China"

通信作者："Wan, WJ; Hu, K (通讯作者)，Chongqing Med Univ, Chongqing Eye Inst, Chongqing Key Lab Prevent & Treatment Major Blindi, Affiliated Hosp 1,Chongqing Branch,Municipal Div,N, Chongqing 400016, Peoples R China."

来源：FASEB JOURNAL

ESI学科分类：BIOLOGY & BIOCHEMISTRY

WOS号：WOS:001286728600001

JCR分区：Q1

影响因子：4.8

年份：2024

卷号：38

期号：15

开始页：　

结束页：　

文献类型：Article

关键词：apoptosis; calcium; ciliary muscle; mitochondria; oxidative stress

摘要："The ciliary muscle constitutes a crucial element in refractive regulation. Investigating the pathophysiological mechanisms within the ciliary muscle during excessive contraction holds significance in treating ciliary muscle dysfunction. A guinea pig model of excessive contraction of the ciliary muscle induced by drops pilocarpine was employed, alongside the primary ciliary muscle cells was employed in in vitro experiments. The results of the ophthalmic examination showed that pilocarpine did not significantly change refraction and axial length during the experiment, but had adverse effects on the regulatory power of the ciliary muscle. The current data reveal notable alterations in the expression profiles of hypoxia inducible factor 1 (HIF-1 alpha), ATP2A2, P53, alpha-SMA, Caspase-3, and BAX within the ciliary muscle of animals subjected to pilocarpine exposure, alongside corresponding changes observed in cultured cells treated with pilocarpine. Augmented levels of ROS were detected in both tissue specimens and cells, culminating in a significant increase in cell apoptosis in in vivo and in vitro experiments. Further examination revealed that pilocarpine induced an increase in intracellular Ca2+ levels and disrupted MMP, as evidenced by mitochondrial swelling and diminished cristae density compared to control conditions, concomitant with a noteworthy decline in antioxidant enzyme activity. However, subsequent blockade of Ca2+ channels in cells resulted in downregulation of HIF-1 alpha, ATP2A2, P53, alpha-SMA, Caspase-3, and BAX expression, alongside ameliorated mitochondrial function and morphology. The inhibition of Ca2+ channels presents a viable approach to mitigate ciliary cells damage and sustain proper ciliary muscle function by curtailing the mitochondrial damage induced by excessive contractions. Ciliary muscle overregulation causes apoptosis and senescence of ciliary muscle cells, which is clinically manifested as difficulty in visual accommodation. The molecular mechanism is manifested by intracellular accumulation of calcium ions caused by hypercontraction leading to ciliary muscle mitochondrial damage and increased cellular dysregulation. Nifedipine attenuates these cellular injuries by blocking calcium channels.image"

基金机构："MOST | National Natural Science Foundation of China (NSFC) [82371098]; Foundation of Chongqing Science and Technology Commission of China [cstc2021jcyj- msxm3178, CSTB2022NSCQ-MSX1561]; Chongqing Talent Plan ""Contract program"" [cstc2022ycjh-bgzxm0121]; Natural Science Foundation Project of Chongqing, Chongqing Science and Technology Commission [2024ZDXM033, 2024GDRC005]; Municipal subsidies for disease prevention and control [1-02-02-czzx2151, 1-02-02-czzx2150]"

基金资助正文："MOST | National Natural Science Foundation of China (NSFC), Grant/Award Number: 82371098; the Project Foundation of Chongqing Science and Technology Commission of China, Grant/Award Number: cstc2021jcyj- msxm3178 and CSTB2022NSCQ-MSX1561; Chongqing Talent Plan ""Contract program"", Grant/Award Number: cstc2022ycjh-bgzxm0121; Natural Science Foundation Project of Chongqing, Chongqing Science and Technology Commission, Grant/Award Number: 2024ZDXM033 and 2024GDRC005; Municipal subsidies for disease prevention and control in 2021, Grant/Award Number: 1-02-02-czzx2151 and 1-02-02-czzx2150"