Dataset Information

Chloroquine differentially modulates coronary vasodilation in control and diabetic mice.

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 eNOS^Thr495 (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.

SUBMITTER: Zhang Q

PROVIDER: S-EPMC6989957 | biostudies-literature | 2020 Jan

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Chloroquine differentially modulates coronary vasodilation in control and diabetic mice.

Zhang Qian Q Tsuji-Hosokawa Atsumi A Willson Conor C Watanabe Makiko M Si Rui R Lai Ning N Wang Ziyi Z Yuan Jason X-J JX Wang Jian J Makino Ayako A

British journal of pharmacology 20200108 2

<h4>Background and purpose</h4>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.<h4>Experimental approach</h4>We isolated coronar ...[more]

PMID: 31503328

Similar Datasets

Project description:Inhalational exposure to crystalline silica is linked to several debilitating systemic autoimmune diseases characterized by a prominent humoral immune component, but the mechanisms by which silica induces autoantibodies is poorly understood. To better understand how silica lung exposure breaks B cell tolerance and unleashes autoreactive B cells, we exposed both wildtype mice of healthy C57BL/6 and lupus-prone BXSB, MRL, and NZB strains and mice carrying an autoantibody transgene on each of these backgrounds to instilled silica or vehicle and monitored lung injury, autoimmunity, and B cell fate. Silica exposure induced lung damage and pulmonary lymphoid aggregates in all strains, including in genetically diverse backgrounds and in autoantibody transgenic models. In wildtype mice strain differences were observed in specificity of autoantibodies and site of enhanced autoantibody production, consistent with genetic modulation of the autoimmune response to silica. The unique autoantibody transgene reporter system permitted the in vivo fate of autoreactive B cells and tolerance mechanisms to be tracked directly, and demonstrated the presence of transgenic B cells and antibody in pulmonary lymphoid aggregates and bronchoalveolar lavage fluid, respectively, as well as in spleen and serum. Nonetheless, B cell enumeration and transgenic antibody quantitation indicated that B cell deletion and anergy were intact in the different genetic backgrounds. Thus, silica exposure sufficient to induce substantial lung immunopathology did not overtly disrupt central B cell tolerance, even when superimposed on autoimmune genetic susceptibility. This suggests that silica exposure subverts tolerance at alternative checkpoints, such as regulatory cells or follicle entry, or requires additional interactions or co-exposures to induce loss of tolerance. This possibility is supported by results of differentiation assays that demonstrated transgenic autoantibodies in supernatants of Toll-like receptor (TLR)7/TLR9-stimulated splenocytes harvested from silica-exposed, but not vehicle-exposed, C57BL/6 mice. This suggests that lung injury induced by silica exposure has systemic effects that subtly alter autoreactive B cell regulation, possibly modulating B cell anergy, and that can be unmasked by superimposed exposure to TLR ligands or other immunostimulants.

Project description:We previously generated separate lines of transgenic mice that specifically overexpress either the Fibroblast growth factor (FGF)-2 low-molecular-mass isoform (Tg(LMW)) or the high-mass isoforms (Tg(HMW)) in the osteoblast lineage. Vector/control (Tg(Vector)) mice were also made. Here we report the use of isolated calvarial osteoblasts (COBs) from those mice to investigate whether the FGF-2 protein isoforms differentially modulate bone formation in vitro. Our hypothesis states that FGF-2 isoforms specifically modulate bone morphogenetic protein 2 (BMP-2) function and subsequently bone differentiation genes and their related signaling pathways. We found a significant increase in alkaline phosphatase-positive colonies in Tg(LMW) COBs compared with Tg(Vector) controls. BMP-2 treatment significantly increased mineralized colonies in Tg(Vector) and Tg(LMW) COBs. BMP-2 caused a further significant increase in mineralized colonies in Tg(LMW) COBs compared with Tg(Vector) COBs but did not increase alkaline phosphatase-positive colonies in Tg(HMW) COBs. Time-course studies showed that BMP-2 caused a sustained increase in phosphorylated mothers against decapentaplegic-1/5/8 (Smad/1/5/8), runt-related transcription factor-2 (Runx-2), and osterix protein in Tg(LMW) COBs. BMP-2 caused a sustained increase in phospho-p38 MAPK in Tg(Vector) but only a transient increase in Tg(LMW) and Tg(HMW) COBs. BMP-2 caused a transient increase in phospho-p44/42 MAPK in Tg(Vector) COBs and no increase in Tg(LMW) COBs, but a sustained increase was found in Tg(HMW) COBs. Basal expression of FGF receptor 1 protein was significantly increased in Tg(LMW) COBs relative to Tg(Vector) COBs, and although BMP-2 caused a transient increase in FGF receptor 1 expression in Tg(Vector) COBs and Tg(HMW) COBs, there was no further increase Tg(LMW) COBs. Interestingly, although basal expression of FGF receptor 2 was similar in COBs from all genotypes, BMP-2 treatment caused a sustained increase in Tg(LMW) COBs but decreased FGF receptor 2 in Tg(Vector) COBs and Tg(HMW) COBs.

Dataset Information

Chloroquine differentially modulates coronary vasodilation in control and diabetic mice.

Background and purpose

Experimental approach

Key results

Conclusions and implications

Publications

Chloroquine differentially modulates coronary vasodilation in control and diabetic mice.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets