Vascular injury associated with ethanol intake is driven by AT1 receptor and mitochondrial dysfunction

by Selleckchem | Jan 19 2024

Background: Renin-angiotensin (Ang II)-aldosterone system (RAAS) is crucial for the cardiovascular risk associated with excessive ethanol consumption. Disturbs in mitochondria have been implicated in multiple cardiovascular diseases. However, if mitochondria dysfunction contributes to ethanol-induced vascular dysfunction is still unknown. We investigated whether ethanol leads to vascular dysfunction via RAAS activation, mitochondria dysfunction, and mitochondrial reactive oxygen species (mtROS).

Methods: Male C57/BL6J or mt-keima mice (6-8-weeks old) were treated with ethanol (20% vol./vol.) for 12 weeks with or without Losartan (10 mg/kg/day).

Results: Ethanol induced aortic hypercontractility in an endothelium-dependent manner. PGC1α (a marker of biogenesis), Mfn2, (an essential protein for mitochondria fusion), as well as Pink-1 and Parkin (markers of mitophagy), were reduced in aortas from ethanol-treated mice. Disturb in mitophagy flux was further confirmed in arteries from mt-keima mice. Additionally, ethanol increased mtROS and reduced SOD2 expression. Strikingly, losartan prevented vascular hypercontractility, mitochondrial dysfunction, mtROS, and restored SOD2 expression. Both MnTMPyP (SOD2 mimetic) and CCCP (a mitochondrial uncoupler) reverted ethanol-induced vascular dysfunction. Moreover, L-NAME (NOS inhibitor) and EUK 134 (superoxide dismutase/catalase mimetic) did not affect vascular response in ethanol group, suggesting that ethanol reduces aortic nitric oxide (NO) and H2O2 bioavailability. These responses were prevented by losartan.

Conclusion: AT1 receptor modulates ethanol-induced vascular hypercontractility by promoting mitochondrial dysfunction, mtROS, and reduction of NO and H2O2 bioavailability. Our findings shed a new light in our understanding of ethanol-induced vascular toxicity and open perspectives of new therapeutic approaches for patients with disorder associated with abusive ethanol drinking.

Comments:

This study you're referencing delves into the impact of ethanol on the vascular system, particularly focusing on the role of the renin-angiotensin-aldosterone system (RAAS), mitochondria dysfunction, and mitochondrial reactive oxygen species (mtROS) in causing vascular issues. The experiment involved treating mice with ethanol and observing its effects on aortic function, mitochondria health, and oxidative stress, alongside interventions like Losartan and various mimetics to understand the underlying mechanisms.

The key findings indicate that ethanol induces hypercontractility in the aorta via endothelium-dependent pathways. This effect seems to involve a reduction in markers associated with mitochondrial health, such as PGC1α (related to biogenesis), Mfn2 (involved in mitochondria fusion), as well as Pink-1 and Parkin (markers of mitophagy). These changes suggest disturbances in both mitochondrial structure and clearance of damaged mitochondria in response to ethanol.

Furthermore, ethanol was observed to increase mtROS while reducing the expression of SOD2, an enzyme that scavenges reactive oxygen species within mitochondria. Interestingly, the administration of Losartan, an AT1 receptor blocker, prevented the vascular hypercontractility, restored mitochondrial function, decreased mtROS, and reinstated SOD2 expression. This suggests that the AT1 receptor modulation plays a pivotal role in ethanol-induced vascular dysfunction through its influence on mitochondrial health and oxidative stress.

Additionally, interventions like MnTMPyP (SOD2 mimetic) and CCCP (a mitochondrial uncoupler) were able to reverse ethanol-induced vascular dysfunction, further implicating the involvement of mitochondria and ROS in this process.Moreover, the study indicates that ethanol reduces the bioavailability of nitric oxide (NO) and hydrogen peroxide (H2O2) in the aorta, which could contribute to the observed vascular dysfunction. This reduction in NO and H2O2 levels was not affected by L-NAME (a NOS inhibitor) or EUK 134 (a superoxide dismutase/catalase mimetic) but was prevented by Losartan.

Overall, the study suggests that ethanol-induced vascular toxicity involves multiple pathways, including RAAS activation, mitochondrial dysfunction, and alterations in ROS and bioavailability of NO and H2O2. The findings open avenues for potential therapeutic approaches for disorders associated with excessive ethanol consumption by targeting the RAAS or mitochondrial function to mitigate vascular damage.