Barbosa, G. S. | Search bioRxiv

bioRxiv2023

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

BackgroundRenin-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). MethodsMale 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). ResultsEthanol induced aortic hypercontractility in an endothelium-dependent manner. PGC1 (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. ConclusionAT1 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.

pharmacology and toxicology↗

bioRxiv2023

Suppressed vascular Rho-kinase activation is a protective cardiovascular mechanism in obese female mice

BackgroundObesity is the number one cardiovascular risk factor for both men and women and is a complex condition. Although a sex dimorphism on vascular function has already been noted, the underlying processes remain unclear. The Rho-kinase pathway has a unique role in controlling vascular tone, and in obese male mice, hyperactivation of this system results in worsened vascular constriction. We investigated whether female mice exhibit decreased Rho-kinase activation as a protective mechanism in obesity. MethodsWe exposed male and female mice to a high-fat diet (HFD) for 12 weeks. At the end, energy expenditure, glucose tolerance, adipose tissue inflammation, and vascular function were investigated. ResultsMale mice were more sensitive to HFD-induced body weight gain, glucose tolerance, and inflammation than female mice. After establishing obesity, female mice demonstrated increase in energy expenditure, characterized by an increase in heat, whereas male mice did not. Interestingly, obese female mice, but not male, displayed attenuated vascular contractility to different agonists, such difference was blunted by inhibition of Rho-kinase. Finally, aortae from obese female mice, but not male, responded prematurely to Rho-kinase inhibitor, which was accompanied by a suppressed Rho-kinase activation, measured by western blot. ConclusionIn obesity, female mice demonstrate a vascular protective mechanism - suppression of vascular Rho-kinase - to minimize the cardiovascular risk associated with obesity, whereas male mice do not generate any adaptive response. Future investigations can help to understand how Rho-kinase becomes suppressed in female during obesity.

physiology↗