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 (TAL-LYHO/Jng [TH] mice, a spontaneous type 2 diabetic mouse model) were used for the molecular biological or cytosolic NO and Ca 2+ 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 Ca 2+ 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.

Covid-19 treatment update: follow the scientific evidence

“…Chloroquine has been shown to differentially modulate coronary arterial vasodilation in diabetic mice [8]. In humans, it decreases nitric oxide production in coronary artery endothelial cells.…”

Mechanisms Underlying the Effects of Chloroquine on Red Blood Cells Metabolism

“…In the presence of CQ, the reduced ATP synthesis and release from RBCs leads to a decrease in NO synthesis and diffusion, which in turn negatively affects vasodilation input. This hypothesis is partly confirmed by Perecko et al who showed that both chloroquine and its hydroxyderivative, hydroxychloroquine, inhibited NO production in the immortalized mouse macrophage cell line RAW 264.7 and mouse bone marrow-derived macrophages [ 51 , 52 ]. The above reports open new points of research on the side effects of the drug, especially in patients with coronary or cardiovascular diseases.…”

Immune Modulation as a Therapeutic Option During the SARS-CoV-2 Outbreak: The Case for Antimalarial Aminoquinolines

“…CQ/HCQ effects differ between normal and diseased cardiovascular systems. In a murine model, CQ inhibited endothelial-dependent coronary vascular relaxation in control mice but increased it in diabetic TALLYHO/Jng mice ( 97 ), underscoring the special link between CQ/HCQ and type 2 diabetes which will be detailed below.…”

“…Finally, as a broad-spectrum agonist of TAS2R, CQ increases the intracellular concentration of Ca 2+ in airway smooth muscle cells through PLCβ (Phospholipase Lipase C β) activation, inositol-trisphosphate (IP3) production and binding to endoplasmic reticulum IP3 receptor, followed by the mobilization of Ca 2+ stores ( 53 ). As a result, CQ administration results in airway smooth muscle relaxation, even in precontracted airways, thus reversing airway obstruction in human, murine, and guinea pig models ( 97 ).…”