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). 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.

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

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).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).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.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. 

Pore-Forming VDAC Proteins of the Outer Mitochondrial Membrane: Regulation and Pathophysiological Role

Aim To explore the association between oxidative balance score (OBS) and cardiovascular diseases (CVD) in patients with hypertension, and further clarify the mediating role of methylmalonic acid (MMA) in the relationship between OBS and CVD risk. Methods We included 4,137 participants with hypertension from the 2011–2014 National Health and Nutrition Examination Survey cohort. The study endpoint was the incidence of CVD in patients with hypertension. OBS was calculated based on 16 dietary and 4 lifestyle components. Weighted multivariable logistic regression models were adopted to assess the associations between OBS and CVD risk, OBS and MMA levels, and MMA levels and CVD risk. Odds ratios (OR) and 95% confidence interval (CI) were estimated. We used distribution-of-product method to test for mediation effect, with a presence of mediation indicated by 95% CI that does not include 0 for the distribution-of-product method and 95% CI that does not include 1 for the indirect effect. Results Totally 812 developed CVD. In weighted multivariable logistic regression models, lower OBS category (OBS &amp;lt; 15.72) was associated with increased odds of CVD (OR = 1.53, 95%CI: 1.17–2.01) and MMA levels (OR = 1.32, 95%CI: 1.06–1.65), respectively, compared with higher OBS category as reference. A positive relationship between higher MMA levels (≥154.90 nmol/L) and CVD risk was observed (OR = 1.34, 95%CI: 1.07–1.68). Importantly, according to the distribution-of-product test, a potential mediating effect of MMA on the relationship between OBS and CVD was found (OR = 1.08, 95%CI: 1.01–1.19), with a 95% CI for distribution-of-product of 0.08 (95% CI: 0.01–0.17). The mediated proportion was 17.8%. Subgroup analysis revealed a mediating effect of MMA in individuals with dyslipidemia, with a mediated proportion of 14.9%. Conclusion MMA plays a critical mediating role in the pathway between OBS and CVD risk. 

Association between oxidative balance score and cardiovascular diseases: mediating analysis of methylmalonic acid based on the NHANES database

Natural compounds as therapeutic agents: Addressing global health challenges

Current advances of Mitochondrial dysfunction and cardiovascular disease and promising therapeutic strategies

Atherosclerosis (AS) is the major factor of cardiovascular disease (CVD) and is characterized by a progressive and chronic inflammatory process in the arterial wall. Recent studies have shown that disruption of the mitochondrial membrane potential (deltapsi (m)) directly affects the electron transport chain (ETC), which in turn leads to oxidative stress, and furthermore, its alteration leads to apoptosis and activation of the NLRP3 inflammasome, thereby promoting the development of AS. Here, this review describes how deltapsi (m) contributes to the development of AS by mediating oxidative stress, apoptosis, and NLRP3 inflammasome activation, and potential AS intervention strategies by targeting oxidative stress, apoptosis, and NLRP3 inflammasome activation induced by deltapsi (m).

Atherosclerosis: from the disruption of mitochondrial membrane potential to the potential interventional strategies.

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Current advances of Mitochondrial dysfunction and cardiovascular disease and promising therapeutic strategies

Atherosclerosis: from the disruption of mitochondrial membrane potential to the potential interventional strategies.