Mitochondrial mitophagy protection combining rivaroxaban and aspirin in high glucose-exposed human coronary artery endothelial cell. An in vitro study

Abstract

Purpose Combination of Rivaroxaban plus Aspirin improved cardiovascular outcome in patients with stable cardiovascular disease. The aim was to determine if Rivaroxaban and acetylsalicylic acid alone or in combination may protect mitochondrial mitophagy in human coronary artery endothelial cells (HCAEC) exposed to D-glucose. Methods HCAEC were incubated under different conditions: 5 mmol/L glucose D-glucose (control), 30 mmol/L D-Glucose with and without 50 nmol/L Rivaroxaban (Rivaroxaban), 0.33 mmol/L ASA (ASA) or Rivaroxaban (12.5 nmol/L)+ASA (0.33 mmol/L; (Riva+ASA). Results HCAEC incubated with D-glucose showed an increased Factor Xa expression. The mitochondrial content of Pink-1 and Parkin were significantly reduced in high glucose-incubated HCAEC compared to control. Rivaroxaban+ASA significantly increased the mitochondrial content of Pink-1 and Parkin, and the mitochondrial membrane potential compared to D-Glucose group. Both ASA alone and Riva+ASA reduced reactive oxygen species (ROS) and tissue factor production induced by high glucose exposure. Conclusion Under high glucose condition combining Rivaroxaban+ASA increased the mitochondrial content of Pink-1 and Parkin, restored mitochondria membrane potential and reduced ROS and tissue factor expression in HCAEC. It suggests potential effects induced by dual use of Rivaroxaban and ASA on the coronary endothelium subjected to high glucose condition.

Mitochondrial dysfunction in vascular endothelial cells and its role in atherosclerosis

“…Following mitochondrial damage and dysfunction, mitophagy plays a pivotal role in maintaining endothelial homeostasis by eliminating damaged or dysfunctional mitochondria, which can decrease the release of mitochondrial mtDAMPs and ROS to the cytoplasm from damaged or dysfunctional mitochondria, and attenuating endothelial disorder ( Figure 3 ) (Y. Chen Y et al, 2022 ; Zekri-Nechar et al, 2022 ; Zhang et al, 2008 ). Mitochondrial dysfunction induced by atherosclerosis-related risk factors in ECs is an important mechanism of atherosclerotic initiation and progression.…”

“…Following mitochondria damage, mitophagy removes damaged and dysfunctional mitochondria to maintain intracellular homeostasis in the cardiovascular system (Y. Chen Y et al, 2022 ; He et al, 2019 ; Huynh and Heo, 2021 ; Tu et al, 2022 ; Yang et al, 2022 ).Mitophagy-mediated elimination of damaged mitochondria alleviates mitochondrial damaged-induced EC injury or dysfunction ( Bhogal et al, 2018 ; Zekri-Nechar et al, 2022 ).…”

Distinct pleiotropic effects of direct oral anticoagulants on cultured endothelial cells: a comprehensive review

“…Interestingly, co-administration of rivaroxaban enhanced the effect of aspirin. These findings show that rivaroxaban and aspirin combined can potentially support the endothelium from hyperglycemic conditions due to mitochondrial mitophagy protection (Zekri-Nechar et al, 2022a). Wu et al (2015) by using in vivo and in vitro models of diabetes aimed to examine the impact of rivaroxaban in angiogenesis.…”

L‐carnitine alleviates cardiac microvascular dysfunction in diabetic cardiomyopathy by enhancing PINK1‐Parkin‐dependent mitophagy through the CPT1a‐PHB2‐PARL pathways

“…Most studies have demonstrated that PINK1 and Parkin are downregulated in ECs exposed to high glucose (HG) and/ or free fatty acids (FFAs), whereas one study has revealed that PINK1 and Parkin are upregulated in the aortic endothelium of obese and diabetic mice. [21][22][23][24] Given these discrepancies, the abovementioned results need further confirmation in cardiac microcirculation under diabetic stress. The import of PINK1 into the mitochondria is an initial step in PINK1-Parkin-dependent mitophagy, after L-carnitine through the inhibition of PARL detachment from PHB2.…”

“…However, only the PINK1‐Parkin axis‐dependent pathway has been preliminarily introduced into ECs in diabetes mellitus or hyperglycemia, and the results remain controversial. Most studies have demonstrated that PINK1 and Parkin are downregulated in ECs exposed to high glucose (HG) and/or free fatty acids (FFAs), whereas one study has revealed that PINK1 and Parkin are upregulated in the aortic endothelium of obese and diabetic mice 21–24 . Given these discrepancies, the abovementioned results need further confirmation in cardiac microcirculation under diabetic stress.…”