Subacute administration of cilostazol modulates PLC-γ/PKC-α/p38/NF-kB pathway and plays vascular protective effects through eNOS activation in early stages of atherosclerosis development

Stephani Correia Brazão; Gabriel Ferreira Lima; Lis Jappour Autran; Ana Beatriz Araújo Mendes; Beatriz Alexandre Dos Santos; Dangelo Carlo Magliano; Fernanda Carla Ferreira de Brito; Nadia Alice Vieira Motta

doi:10.1016/j.lfs.2023.122082

Subacute administration of cilostazol modulates PLC-γ/PKC-α/p38/NF-kB pathway and plays vascular protective effects through eNOS activation in early stages of atherosclerosis development

Life Sci. 2023 Nov 1:332:122082. doi: 10.1016/j.lfs.2023.122082. Epub 2023 Sep 16.

Authors

Stephani Correia Brazão¹, Gabriel Ferreira Lima¹, Lis Jappour Autran¹, Ana Beatriz Araújo Mendes¹, Beatriz Alexandre Dos Santos², Dangelo Carlo Magliano², Fernanda Carla Ferreira de Brito³, Nadia Alice Vieira Motta¹

Affiliations

¹ Laboratory of Experimental Pharmacology (LAFE), Department of Physiology and Pharmacology, Biomedical Institute, Fluminense Federal University (UFF), Room 310, Valonguinho, 24020-150 Niterói, RJ, Brazil.
² Laboratory of Morphological and Metabolic Analyses, Department of Morphology Biomedical Institute, Fluminense Federal University (UFF), Brazil.
³ Laboratory of Experimental Pharmacology (LAFE), Department of Physiology and Pharmacology, Biomedical Institute, Fluminense Federal University (UFF), Room 310, Valonguinho, 24020-150 Niterói, RJ, Brazil. Electronic address: brito_fernanda@id.uff.br.

PMID: 37722587
DOI: 10.1016/j.lfs.2023.122082

Abstract

Aims: Hypercholesterolemia is an important risk factor for development of cardiovascular disturbances, such as atherosclerosis, and its treatment remains challenging in modern medicine. Cilostazol is a selective inhibitor of phosphodiesterase 3 clinically prescribed for intermittent claudication treatment. Due to its pleiotropic properties, such as lipid lowering, anti-inflammatory, and antioxidant effects, the therapeutic repurposing of cilostazol has become a strategic approach for atherosclerosis treatment. This study aimed to investigate the effects of subacute administration of cilostazol on the aortas of hypercholesterolemic rats, focusing on the signaling pathways involved in these actions.

Main methods: A murine model of hypercholesterolemia was employed to mimic the early stages of atherosclerosis development. Vascular reactivity assays were performed on thoracic aorta rings to assess the vascular response, as well as the non-invasive blood pressure was evaluated by plethysmography method. Pro-inflammatory markers and malondialdehyde (MDA) levels were measured to investigate the anti-inflammatory and antioxidant effects of cilostazol. Western Blot analysis was performed in aortas homogenates to evaluate the role of cilostazol on PLC-γ/PKC-α/p38-MAPK/IκB-α/NF-кB and PKA/eNOS/PKG pathways.

Key findings: The hypercholesterolemic diet induced the production of pro-inflammatory mediators such as TNF-α, TXB₂, VCAM, and worsened vascular function, marked by increased contractile response, decreased maximum relaxation, and elevated systolic and diastolic blood pressure. Cilostazol seems to counteract the deleterious effects promoted by hypercholesterolemic diet, showing important anti-inflammatory and vasculoprotective properties possibly through the inhibition of the PLC-γ/PKC-α/p38-MAPK/IκB-α/NF-кB pathway and activation of the PKA/eNOS/PKG pathway.

Significance: Cilostazol suppressed hypercholesterolemia-induced vascular dysfunction and inflammation. Our data suggest the potential repurposing of cilostazol as a pharmacological treatment for atherosclerosis.

Keywords: Atherosclerosis; Cilostazol; Endothelial dysfunction; Hypercholesterolemia; Vascular reactivity.