Biology subjects

Awata, W. M. C.

Publications and source records attributed to Awata, W. M. C..

4 recordsLinked to original sources

bioRxiv2023

Role Of The C-C Motif Chemokine Ligand 5 (CCL5) And Its Receptor, C-C Motif Chemokine Receptor 5 (CCR5) In The Genesis Of Aldosterone-induced Hypertension, Vascular Dysfunction, And End-organ Damage

BackgroundAldosterone, a mineralocorticoid steroid hormone, has been described to initiate cardiovascular diseases by triggering exacerbated sterile vascular inflammation. The functions of C-C Motif Chemokine Ligand 5 (CCL5) and its receptor, C-C Motif Chemokine Receptor 5 (CCR5), are well known in infectious diseases, but their roles in the genesis of aldosterone-induced vascular injury and hypertension are unknown. MethodsWe analyzed the vascular profile, blood pressure, and renal damage in wild-type (CCR5+/+) and CCR5 knockout (CCR5-/-) mice treated with aldosterone (600 {micro}g/kg/day for 14 days) while receiving 1% saline to drink. ResultsHere, we show that CCR5 plays a central role in aldosterone-induced vascular injury, hypertension, and renal damage. Long-term infusion of aldosterone in CCR5+/+ mice resulted in exaggerated CCL5 circulating levels and vascular CCR5 expression. Aldosterone treatment also triggered vascular injury, characterized by endothelial dysfunction and inflammation, hypertension, and renal damage. Mice lacking CCR5 were protected from aldosterone-induced vascular damage, hypertension, and renal injury. Mechanistically, we demonstrated that CCL5 increased NADPH oxidase 1 (Nox1) expression, reactive oxygen species (ROS) formation, NF{kappa}B activation, and inflammation and reduced nitric oxide production in isolated endothelial cells. These effects were abolished by antagonizing CCR5 with Maraviroc. Finally, aortae incubated with CCL5 displayed severe endothelial dysfunction, which is prevented by blocking Nox1, NF{kappa}B, or with Maraviroc treatment. ConclusionsOur data demonstrate that CCL5/CCR5, through activation of NFkB and Nox1, is critically involved in aldosterone-induced vascular and renal damage and hypertension. Our data place CCL5 and CCR5 as potential targets for therapeutic interventions in conditions with aldosterone excess.

pharmacology and toxicology↗

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

Progranulin maintains blood pressure and vascular tone dependent on EphrinA2 and Sortilin1 receptors and eNOS activation

BackgroundThe mechanisms determining vascular tone are still not completely understood, even though it is a significant factor in blood pressure management. Many circulating proteins have a significant impact on controlling vascular tone. Progranulin (PGRN) displays anti-inflammatory effects and has been extensively studied in neurodegenerative illnesses. We investigated whether PGRN sustains the vascular tone that helps regulate blood pressure. MethodsWe used male and female C57BL6/J wild type (PGRN+/+) and B6(Cg)-Grntm1.1Aidi/J (PGRN-/-) to understand the impact of PGRN on vascular contractility and blood pressure. ResultsWe found that male and female PGRN-/- mice display elevated blood pressure followed by hypercontractility to noradrenaline in mesenteric arteries, which are restored by supplementing the mice with recombinant PGRN (rPGRN). In ex vivo experiments, rPGRN attenuated the vascular contractility to noradrenaline in male and female PGRN+/+ arteries, which was blunted by blocking EphrinA2 or Sortlin1. To understand the mechanisms whereby PGRN evokes anti-contractile effects, we inhibited endothelial factors. L-NAME [nitric oxide (NO) synthase (NOS) inhibitor] prevented the PGRN effects, whereas indomethacin (cyclooxygenases inhibitor) only affected the contractility in arteries incubated with vehicle, indicating the PGRN increases nitric oxide and decreases contractile prostanoids. Finally, rPGRN induced endothelial NOS (eNOS) phosphorylation and NO production in isolated mesenteric endothelial cells. ConclusionCirculating PGRN regulates vascular tone and blood pressure via EphrinA2 and Sortlin1 receptors and eNOS activation. Collectively, our data suggest that deficiency in PGRN is a cardiovascular risk factor and that PGRN might be a new therapeutic avenue to treat high blood pressure. Clinical PerspectiveWhat is new? O_LIPGRN displays vascular anti-contractile effects dependent on EphrinA2 and Sortilin1 receptors and nitric oxide formation in male and female C_LIO_LIDeficiency in PGRN triggers high blood pressure and induces vascular dysfunction characterized by hypercontractility to noradrenaline C_LIO_LIPGRN supplementation restores blood pressure and vascular dysfunction in PGRN-deficient mice C_LI What are the clinical implications? O_LIPGRN deficiency is associated with neurodegenerative diseases including neuronal ceroid lipofuscinosis and frontotemporal dementia (FTD). Our study reveals that a lack of PGRN might be associated with vascular dysfunction and high blood pressure C_LIO_LISupplementation with PGRN might be a potential therapeutic route to treat high blood pressure and diseases associated with vascular dysfunction C_LIO_LIReduction in PGRN might be a target to screen for higher cardiovascular risk C_LI

pharmacology and toxicology↗

bioRxiv2022

Progression of vascular function and blood pressure in a mouse model of Kawasaki disease

BackgroundKawasaki disease (KD) is a systemic vasculitis of childhood characterized by vascular damage in the acute stage, which can persist into the late stage. Aneurysms, myocardial infarction, and death are long-standing complications associated with KD. The vascular mechanisms in the cardiovascular risk of KD are not fully studied. Herein, we investigated the vascular function and blood pressure regulation in a murine model of KD. Material and methodsWe used the Candida albicans water soluble (CAWS) fraction model. Mice were injected with 4 mg CAWS for five consecutive days and separated into 3 groups. Control (Ctrl): water injected for 5 days; CAWS 7 days (C7): CAWS injected for 5 days plus 2 additional days of wait; CAWS 28 days (C28): CAWS injected for 5 days plus 23 additional days of wait. Blood pressure was analyzed via radiotelemetry. In the end, the heart and arteries were harvested for vasculitis characterization and vascular function in a wire myograph. Rat Aortic Vascular Smooth Muscle cells (RASMC) were used to dissect the molecular mechanisms in vitro. Main findingsC7 presented elevated inflammatory markers in the coronary area (CA) and abdominal aortae (AA), whereas C28 showed severe vasculitis in CA and AA. No difference was found in blood pressure and heart rate. Vascular dysfunction characterized by higher contractility to norepinephrine (NA) in C7 and C28 was abolished by blocking nitric oxide (NO) production, reactive oxygen species (ROS), and cyclooxygenase (COX)-derived products. RASMC treated with CAWS (10ug/mL) presented an increase in COX2 expression, which was prevented by pre-treating the cells with TAK-242 [Toll like receptor 4 (TLR4) antagonist, 3x10-5M]. ConclusionOur data indicate that the murine model of KD is associated with vascular dysfunction likely dependent on COX-derived products, oxidant properties, and NO bioavailability. Furthermore, VSMC may present an important role in the genesis of vascular dysfunction and vasculitis via the TLR4 pathway. Finally, the CAWS model seems not to be appropriate to study KD-associated shock. More studies are necessary to understand whether vascular dysfunction and COXs are triggers for vasculitis.

pharmacology and toxicology↗