The fibrate gemfibrozil is a NO‐ and haem‐independent activator of soluble guanylyl cyclase: in vitro studies

Abstract

BACKGROUND AND PURPOSEFibrates are a class of drugs widely used to treat dyslipidaemias. They regulate lipid metabolism and act as PPARα agonists. Clinical trials demonstrate that besides changes in lipid profiles, fibrates decrease the incidence of cardiovascular events, with gemfibrozil exhibiting the most pronounced benefit. This study aims to characterize the effect of gemfibrozil on the activity and function of soluble guanylyl cyclase (sGC), the key mediator of NO signalling. EXPERIMENTAL APPROACHHigh-throughput screening of a drug library identified gemfibrozil as a direct sGC activator. Activation of sGC is unique to gemfibrozil and is not shared by other fibrates. KEY RESULTSGemfibrozil activated purified sGC, induced endothelium-independent relaxation of aortic rings and inhibited platelet aggregation. Gemfibrozil-dependent activation was absent when the sGC haem domain was deleted, but was significantly enhanced when sGC haem was lacking or oxidized. Oxidation of sGC haem enhanced the vasoactive and anti-platelet effects of gemfibrozil. Gemfibrozil competed with the haem-independent sGC activators ataciguat and cinaciguat. Computational modelling predicted that gemfibrozil occupies the space of the haem group and interacts with residues crucial for haem stabilization. This is consistent with structure-activity data which revealed an absolute requirement for gemfibrozil's carboxyl group. CONCLUSIONS AND IMPLICATIONSThese data suggest that in addition to altered lipid and lipoprotein state, the cardiovascular preventive benefits of gemfibrozil may derive from direct activation and protection of sGC function. A sGC-directed action may explain the more pronounced cardiovascular benefit of gemfibrozil observed over other fibrates and some of the described side effects of gemfibrozil.

Targeting vascular (endothelial) dysfunction

“…Similar beneficial effects were described for endothelin‐1 receptor antagonists (Clozel, ; Thorin and Clozel, ). Gemfibrozil is a lipid‐lowering drug that also activates sGC in a nitric oxide‐ and haem‐independent fashion, which may explain the more pronounced cardiovascular benefit observed with this drug as compared to other members of the fibrate group of drugs (Sharina et al , ).…”

Pharmacological preconditioning with gemfibrozil preserves cardiac function after heart transplantation

“…Although sGC activation is a promising way to go, these compounds have not been approved for clinical use yet. The widely used fibrate gemfibrozil has been recently described as a NO- and haem-independent activator of sGC 13 . Sharina et al .…”

“…Sharina et al . suggested that the mechanism of action of gemfibrozil was similar to haem-mimicking sGC-activators, however it was less potent than cinaciguat or ataciguat 13 . The advantage of gemfibrozil is that it has been approved for decades and used in the pharmacological management of hyperlipidemia 13 .…”

“…Interestingly Sharina et al . 13 described an existing side effect of GEM in 2015, i.e. activation of the sGC in an in vitro setup.…”

Effect of Peroxisome Proliferator-Activated Receptor-Alpha-Agonists on Diabetes-Induced Acute Kidney Injury: Role of Oxidative Stress and Hyperlipidemia

“…A recent study revealed the mechanism of cardioprotection by gemfibrozil by attenuating oxidative stress. Importantly, research exhibiting the most pronounced benefits of gemfibrozil in preventing vascular events by direct activation and protection of guanylyl cyclase (sGC) the key mediator of NO signaling [4]. The gemfibrozil mediated activation of guanylyl cyclase may be a rational concept to attenuate the oxidative stress and hyperlipidemia.…”