OP2113, a new drug for chronic hypoxia‐induced pulmonary hypertension treatment in rat

Abstract

Background and PurposePulmonary hypertension (PH) is a cardiovascular disease characterised by an increase in pulmonary arterial (PA) resistance leading to right ventricular (RV) failure. Reactive oxygen species (ROS) play a major role in PH. OP2113 is a drug with beneficial effects on cardiac injuries that targets mitochondrial ROS. The aim of the study was to address the in vivo therapeutic effect of OP2113 in PH.Experimental ApproachPH was induced by 3 weeks of chronic hypoxia (CH‐PH) in rats treated with OP2113 or its vehicle via subcutaneous osmotic mini‐pumps. Haemodynamic parameters and both PA and heart remodelling were assessed. Reactivity was quantified in PA rings and in RV or left ventricular (LV) cardiomyocytes. Oxidative stress was detected by electron paramagnetic resonance and western blotting. Mitochondrial mass and respiration were measured by western blotting and oxygraphy, respectively.Key ResultsIn CH‐PH rats, OP2113 reduced the mean PA pressure, PA remodelling, PA hyperreactivity in response to 5-HT, the contraction slowdown in RV and LV and increased the mitochondrial mass in RV. Interestingly, OP2113 had no effect on haemodynamic parameters, both PA and RV wall thickness and PA reactivity, in control rats. Whereas oxidative stress was evidenced by an increase in protein carbonylation in CH‐PH, this was not affected by OP2113.Conclusion and ImplicationsOur study provides evidence for a selective protective effect of OP2113 in vivo on alterations in both PA and RV from CH‐PH rats without side effects in control rats.

Mitochondrial dysfunction: mechanisms and advances in therapy

“…Certain compounds specifically target the complex I site, including S1QELs and OP2113, inhibiting RET and ROS production without disturbing normal OXPHOS. 214 , 337 – 339 Quinone-based antioxidants, encompassing CoQ analogs idebenone and EPI-743, alongside a water-soluble Vitamin E derivative sonlicromanol (also known as KH176), are employed as a frontline defense against mitochondrial oxidative damage. These antioxidants exert their protective roles by neutralizing reactive oxygen species and safeguarding the activity of glutathione, a crucial antioxidant within cells 340 – 342 Some drugs target MPTP opening and thus reducing RIRR and cell death events, such as classic cyclophilin D (CypD) inhibitor CsA, which occlude the peptidyl-prolyl cis/trans isomerase (PPIase) active site of CypD.…”