Chloroquine differentially modulates coronary vasodilation in control and diabetic mice.

Zhang, Qian; Tsuji-Hosokawa, Atsumi; Willson, Conor; Watanabe, Makiko; Si, Rui; Lai, Ning; Wang, Ziyi; Yuan, Jason X-J; Wang, Jian; Makino, Ayako

BACKGROUND AND PURPOSE Chloroquine (CQ) is a traditional medicine to treat malaria. There is increasing evidence that CQ not only induces phagocytosis but also regulates vascular tone. However, there are few reports investigating the effect of CQ on vascular responsiveness in coronary artery (CA). In this study, we examined whether and how CQ affected endothelium-dependent relaxation (EDR) in CAs under healthy and diabetic status. EXPERIMENTAL APPROACH We isolated CAs from mice and examined endothelium-dependent relaxation (EDR). Human coronary endothelial cells (HCECs) and mouse coronary endothelial cells (MCECs) 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 CQ inhibited endothelium-derived NO (EDNO)-dependent relaxation, but had negligible effect on endothelium-derived hyperpolarization (EDH)-dependent relaxation in CAs of control mice. CQ significantly decreased NO production in control HCECs 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, CQ enhanced EDR in diabetic CAs by, specifically, increasing EDH-dependent relaxation due partly to its augmenting effect on gap junction activity in diabetic MCECs. CONCLUSIONS AND IMPLICATIONS These data indicate that CQ affects vascular relaxation differently under healthy and diabetic status. Therefore, the patients' health condition such as coronary macro- or microvascular disease with or without diabetes must be taken account into the consideration of selecting CQ for the treatment of malaria.