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

Costa, R. M.; Cerqueira, D. M.; Bruder do Nascimento, A.; Alves, J. V.; Awata, W. M. C.; Singh, S.; Kufner, A.; Cifuentes-Pagano, E.; Pagano, P. J.; Ho, J.; Bruder-Nascimento, T.

doi:10.1101/2023.09.22.558020

bioRxiv · 10.1101/2023.09.22.558020

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

Costa, R. M.·Cerqueira, D. M.·Bruder do Nascimento, A.·Alves, J. V.·Awata, W. M. C.·Singh, S.·Kufner, A.·Cifuentes-Pagano, E.·Pagano, P. J.·Ho, J.·Bruder-Nascimento, T.

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Abstract

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.

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Costa, R. M., Cerqueira, D. M., Bruder do Nascimento, A., Alves, J. V., Awata, W. M. C., Singh, S., Kufner, A., Cifuentes-Pagano, E., Pagano, P. J., Ho, J., Bruder-Nascimento, T.. 2023-09-23. 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. https://doi.org/10.1101/2023.09.22.558020

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