Aberrant splicing of Ca V 1.2 calcium channel induced by decreased Rbfox1 enhances arterial constriction during diabetic hyperglycemia.

Autor: Hou W; Key Laboratory of Targeted Intervention of Cardiovascular Disease, Collaborative Innovation Center for Cardiovascular Disease Translational Medicine, Nanjing Medical University, Nanjing, Jiangsu, China.; Department of Physiology, Nanjing Medical University, Nanjing, Jiangsu, China.; The Affiliated Taizhou People's Hospital of Nanjing Medical University, Taizhou School of Clinical Medicine, Nanjing Medical University, Taizhou, Jiangsu, China., Yin S; Key Laboratory of Targeted Intervention of Cardiovascular Disease, Collaborative Innovation Center for Cardiovascular Disease Translational Medicine, Nanjing Medical University, Nanjing, Jiangsu, China.; Department of Physiology, Nanjing Medical University, Nanjing, Jiangsu, China., Li P; Key Laboratory of Targeted Intervention of Cardiovascular Disease, Collaborative Innovation Center for Cardiovascular Disease Translational Medicine, Nanjing Medical University, Nanjing, Jiangsu, China.; Department of Physiology, Nanjing Medical University, Nanjing, Jiangsu, China., Zhang L; Key Laboratory of Targeted Intervention of Cardiovascular Disease, Collaborative Innovation Center for Cardiovascular Disease Translational Medicine, Nanjing Medical University, Nanjing, Jiangsu, China.; Department of Physiology, Nanjing Medical University, Nanjing, Jiangsu, China., Chen T; Key Laboratory of Targeted Intervention of Cardiovascular Disease, Collaborative Innovation Center for Cardiovascular Disease Translational Medicine, Nanjing Medical University, Nanjing, Jiangsu, China.; Department of Physiology, Nanjing Medical University, Nanjing, Jiangsu, China., Qin D; Key Laboratory of Targeted Intervention of Cardiovascular Disease, Collaborative Innovation Center for Cardiovascular Disease Translational Medicine, Nanjing Medical University, Nanjing, Jiangsu, China.; Department of Physiology, Nanjing Medical University, Nanjing, Jiangsu, China., Mustafa AU; Key Laboratory of Targeted Intervention of Cardiovascular Disease, Collaborative Innovation Center for Cardiovascular Disease Translational Medicine, Nanjing Medical University, Nanjing, Jiangsu, China.; Department of Physiology, Nanjing Medical University, Nanjing, Jiangsu, China., Liu C; Key Laboratory of Targeted Intervention of Cardiovascular Disease, Collaborative Innovation Center for Cardiovascular Disease Translational Medicine, Nanjing Medical University, Nanjing, Jiangsu, China.; Department of Physiology, Nanjing Medical University, Nanjing, Jiangsu, China., Song M; Key Laboratory of Targeted Intervention of Cardiovascular Disease, Collaborative Innovation Center for Cardiovascular Disease Translational Medicine, Nanjing Medical University, Nanjing, Jiangsu, China.; Department of Physiology, Nanjing Medical University, Nanjing, Jiangsu, China., Qiu C; Nanjing Comprehensive Stroke Center, Affiliated Nanjing Brain Hospital, Nanjing Medical University, Nanjing, Jiangsu, China., Xiong X; Key Laboratory of Targeted Intervention of Cardiovascular Disease, Collaborative Innovation Center for Cardiovascular Disease Translational Medicine, Nanjing Medical University, Nanjing, Jiangsu, China. xqxiong@njmu.edu.cn.; Department of Physiology, Nanjing Medical University, Nanjing, Jiangsu, China. xqxiong@njmu.edu.cn.; The Affiliated Taizhou People's Hospital of Nanjing Medical University, Taizhou School of Clinical Medicine, Nanjing Medical University, Taizhou, Jiangsu, China. xqxiong@njmu.edu.cn., Wang J; Key Laboratory of Targeted Intervention of Cardiovascular Disease, Collaborative Innovation Center for Cardiovascular Disease Translational Medicine, Nanjing Medical University, Nanjing, Jiangsu, China. juejinwang@njmu.edu.cn.; Department of Physiology, Nanjing Medical University, Nanjing, Jiangsu, China. juejinwang@njmu.edu.cn.; The Affiliated Taizhou People's Hospital of Nanjing Medical University, Taizhou School of Clinical Medicine, Nanjing Medical University, Taizhou, Jiangsu, China. juejinwang@njmu.edu.cn.
Jazyk: angličtina
Zdroj: Cellular and molecular life sciences : CMLS [Cell Mol Life Sci] 2024 Apr 04; Vol. 81 (1), pp. 164. Date of Electronic Publication: 2024 Apr 04.
DOI: 10.1007/s00018-024-05198-z
Abstrakt: Diabetic hyperglycemia induces dysfunctions of arterial smooth muscle, leading to diabetic vascular complications. The Ca V 1.2 calcium channel is one primary pathway for Ca 2+ influx, which initiates vasoconstriction. However, the long-term regulation mechanism(s) for vascular Ca V 1.2 functions under hyperglycemic condition remains unknown. Here, Sprague-Dawley rats fed with high-fat diet in combination with low dose streptozotocin and Goto-Kakizaki (GK) rats were used as diabetic models. Isolated mesenteric arteries (MAs) and vascular smooth muscle cells (VSMCs) from rat models were used to assess K + -induced arterial constriction and Ca V 1.2 channel functions using vascular myograph and whole-cell patch clamp, respectively. K + -induced vasoconstriction is persistently enhanced in the MAs from diabetic rats, and Ca V 1.2 alternative spliced exon 9* is increased, while exon 33 is decreased in rat diabetic arteries. Furthermore, Ca V 1.2 channels exhibit hyperpolarized current-voltage and activation curve in VSMCs from diabetic rats, which facilitates the channel function. Unexpectedly, the application of glycated serum (GS), mimicking advanced glycation end-products (AGEs), but not glucose, downregulates the expression of the splicing factor Rbfox1 in VSMCs. Moreover, GS application or Rbfox1 knockdown dynamically regulates alternative exons 9* and 33, leading to facilitated functions of Ca V 1.2 channels in VSMCs and MAs. Notably, GS increases K + -induced intracellular calcium concentration of VSMCs and the vasoconstriction of MAs. These results reveal that AGEs, not glucose, long-termly regulates Ca V 1.2 alternative splicing events by decreasing Rbfox1 expression, thereby enhancing channel functions and increasing vasoconstriction under diabetic hyperglycemia. This study identifies the specific molecular mechanism for enhanced vasoconstriction under hyperglycemia, providing a potential target for managing diabetic vascular complications.
(© 2024. The Author(s).)
Databáze: MEDLINE
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