Yu-Ying Su1, Huan-Min Li2, Zhen-Xing Yan1, Ming-Chun Li1, Ji-Peng Wei1, Wen-Xia Zheng1, Si-Qin Liu1, Yi-Ting Deng1, Hui-Fang Xie3, Chun-Guang Li4. 1. Department of Neurology, Zhujiang Hospital, Southern Medical University, No. 253, Middle Industrial Avenue, Haizhu District, Guangzhou, Guangdong 510282, PR China. 2. Department of Neurology, Third Affiliated Hospital of Southern Medical University, No. 183, West Zhongshan Avenue, Tianhe District, Guangzhou, Guangdong 510630, PR China. 3. Department of Neurology, Zhujiang Hospital, Southern Medical University, No. 253, Middle Industrial Avenue, Haizhu District, Guangzhou, Guangdong 510282, PR China. Electronic address: xhffhx@126.com. 4. Department of Neurology, Zhujiang Hospital, Southern Medical University, No. 253, Middle Industrial Avenue, Haizhu District, Guangzhou, Guangdong 510282, PR China. Electronic address: lichunguang2005@126.com.
Abstract
AIMS: In the present study, we investigated the roles of renin-angiotensin system (RAS) activation and imbalance of matrix metalloproteinase-9 (MMP-9)/tissue inhibitor of matrix metalloproteinase-1 (TIMP-1) in cold-induced stroke during chronic hypertension, as well as the protective effects of captopril and recombinant human TIMP-1 (rhTIMP-1). MAIN METHODS: Rats were randomly assigned to sham; 2-kidney, 2-clip (2K-2C); 2K-2C + captopril, and 2K-2C + rhTIMP-1 groups. After blood pressure values had stabilized, each group was randomly divided into an acute cold exposure (ACE) group (12-h light at 22 °C/12-h dark at 4 °C) and a non-acute cold exposure (NACE) group (12-h light/12-h dark at 22 °C), each of which underwent three cycles of exposure. Captopril treatment was administered via gavage (50 mg/kg/d), while rhTIMP-1 treatment was administered via the tail vein (60 μg/kg/36 h). KEY FINDINGS: In the 2K-2C group, angiotensin II (AngII) and MMP-9 levels increased in both the plasma and cortex, while no such changes in TIMP-1 expression were observed. Cold exposure further upregulated AngII and MMP-9 levels and increased stroke incidence. Captopril and rhTIMP-1 treatment inhibited MMP-9 expression and activation and decreased stroke incidence in response to cold exposure. SIGNIFICANCE: The present study is the first to demonstrate that cold exposure exacerbates imbalance between MMP-9 and TIMP-1 by activating the RAS, which may be critical in the initiation of stroke during chronic hypertension. In addition, our results suggest that captopril and rhTIMP-1 exert protective effects against cold-induced stroke by ameliorating MMP-9/TIMP-1 imbalance.
AIMS: In the present study, we investigated the roles of renin-angiotensin system (RAS) activation and imbalance of matrix metalloproteinase-9 (MMP-9)/tissue inhibitor of matrix metalloproteinase-1 (TIMP-1) in cold-induced stroke during chronic hypertension, as well as the protective effects of captopril and recombinant humanTIMP-1 (rhTIMP-1). MAIN METHODS:Rats were randomly assigned to sham; 2-kidney, 2-clip (2K-2C); 2K-2C + captopril, and 2K-2C + rhTIMP-1 groups. After blood pressure values had stabilized, each group was randomly divided into an acute cold exposure (ACE) group (12-h light at 22 °C/12-h dark at 4 °C) and a non-acute cold exposure (NACE) group (12-h light/12-h dark at 22 °C), each of which underwent three cycles of exposure. Captopril treatment was administered via gavage (50 mg/kg/d), while rhTIMP-1 treatment was administered via the tail vein (60 μg/kg/36 h). KEY FINDINGS: In the 2K-2C group, angiotensin II (AngII) and MMP-9 levels increased in both the plasma and cortex, while no such changes in TIMP-1 expression were observed. Cold exposure further upregulated AngII and MMP-9 levels and increased stroke incidence. Captopril and rhTIMP-1 treatment inhibited MMP-9 expression and activation and decreased stroke incidence in response to cold exposure. SIGNIFICANCE: The present study is the first to demonstrate that cold exposure exacerbates imbalance between MMP-9 and TIMP-1 by activating the RAS, which may be critical in the initiation of stroke during chronic hypertension. In addition, our results suggest that captopril and rhTIMP-1 exert protective effects against cold-induced stroke by ameliorating MMP-9/TIMP-1 imbalance.
Authors: Cesar A Romero; Shobi Mathew; Benjamin Wasinski; Brian Reed; Aaron Brody; Rachelle Dawood; Michael J Twiner; Candace D McNaughton; Rafael Fridman; John M Flack; Oscar A Carretero; Phillip D Levy Journal: J Clin Hypertens (Greenwich) Date: 2021-03-10 Impact factor: 3.738