Qian Zhang1,2,3, Atsumi Tsuji-Hosokawa2, Conor Willson2, Makiko Watanabe2, Rui Si2, Ning Lai1,3, Ziyi Wang1,4,3, Jason X-J Yuan1,4, Jian Wang4,3, Ayako Makino1,2,4. 1. Department of Medicine, University of California, San Diego, La Jolla, California. 2. Department of Physiology, The University of Arizona, Tucson, Arizona. 3. State Key Laboratory of Respiratory Disease, Guangzhou Institute of Respiratory Disease, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China. 4. Department of Medicine, The University of Arizona, Tucson, Arizona.
Abstract
BACKGROUND AND PURPOSE: Chloroquine is a traditional medicine to treat malaria. There is increasing evidence that chloroquine not only induces phagocytosis but regulates vascular tone. Few reports investigating the effect of chloroquine on vascular responsiveness of coronary arteries have been made. In this study, we examined how chloroquine affected endothelium-dependent relaxation in coronary arteries under normal and diabetic conditions. EXPERIMENTAL APPROACH: We isolated coronary arteries from mice and examined endothelium-dependent relaxation (EDR). Human coronary endothelial cells and mouse coronary endothelial cells isolated from control and diabetic mouse (TALLYHO/Jng [TH] mice, a spontaneous type 2 diabetic mouse model) were used for the molecular biological or cytosolic NO and Ca2+ measurements. KEY RESULTS: Chloroquine inhibited endothelium-derived NO-dependent relaxation but had negligible effect on endothelium-derived hyperpolarization (EDH)-dependent relaxation in coronary arteries of control mice. Chloroquine significantly decreased NO production in control human coronary endothelial cells partly by phosphorylating eNOSThr495 (an inhibitory phosphorylation site of eNOS) and attenuating the rise of cytosolic Ca2+ concentration after stimulation. EDR was significantly inhibited in diabetic mice in comparison to control mice. Interestingly, chloroquine enhanced EDR in diabetic coronary arteries by, specifically, increasing EDH-dependent relaxation due partly to its augmenting effect on gap junction activity in diabetic mouse coronary endothelial cells. CONCLUSIONS AND IMPLICATIONS: These data indicate that chloroquine affects vascular relaxation differently under normal and diabetic conditions. Therefore, the patients' health condition such as coronary macrovascular or microvascular disease, with or without diabetes, must be taken account into the consideration when selecting chloroquine for the treatment of malaria.
BACKGROUND AND PURPOSE:Chloroquine is a traditional medicine to treat malaria. There is increasing evidence that chloroquine not only induces phagocytosis but regulates vascular tone. Few reports investigating the effect of chloroquine on vascular responsiveness of coronary arteries have been made. In this study, we examined how chloroquine affected endothelium-dependent relaxation in coronary arteries under normal and diabetic conditions. EXPERIMENTAL APPROACH: We isolated coronary arteries from mice and examined endothelium-dependent relaxation (EDR). Human coronary endothelial cells and mouse coronary endothelial cells isolated from control and diabeticmouse (TALLYHO/Jng [TH] mice, a spontaneous type 2 diabeticmouse model) were used for the molecular biological or cytosolic NO and Ca2+ measurements. KEY RESULTS:Chloroquine inhibited endothelium-derived NO-dependent relaxation but had negligible effect on endothelium-derived hyperpolarization (EDH)-dependent relaxation in coronary arteries of control mice. Chloroquine significantly decreased NO production in control human coronary endothelial cells partly by phosphorylating eNOSThr495 (an inhibitory phosphorylation site of eNOS) and attenuating the rise of cytosolic Ca2+ concentration after stimulation. EDR was significantly inhibited in diabeticmice in comparison to control mice. Interestingly, chloroquine enhanced EDR in diabetic coronary arteries by, specifically, increasing EDH-dependent relaxation due partly to its augmenting effect on gap junction activity in diabeticmouse coronary endothelial cells. CONCLUSIONS AND IMPLICATIONS: These data indicate that chloroquine affects vascular relaxation differently under normal and diabetic conditions. Therefore, the patients' health condition such as coronary macrovascular or microvascular disease, with or without diabetes, must be taken account into the consideration when selecting chloroquine for the treatment of malaria.
Authors: Kang Wu; Qian Zhang; Xiongting Wu; Wenju Lu; Haiyang Tang; Zhihao Liang; Yali Gu; Shanshan Song; Ramon J Ayon; Ziyi Wang; Kimberly M McDermott; Angela Balistrieri; Christina Wang; Stephen M Black; Joe G N Garcia; Ayako Makino; Jason X-J Yuan; Jian Wang Journal: Br J Pharmacol Date: 2017-10-02 Impact factor: 8.739
Authors: Ayako Makino; Anzhi Dai; Ying Han; Katia D Youssef; Weihua Wang; Reshma Donthamsetty; Brian T Scott; Hong Wang; Wolfgang H Dillmann Journal: Am J Physiol Cell Physiol Date: 2015-08-12 Impact factor: 4.249