Phosphodiesterase-3 inhibitor cilostazol reverses endothelial dysfunction with ageing in rat mesenteric resistance arteries

Artificial Cells, Nanomedicine, and Biotechnology

et al. 2019

Cardiovascular disease is recognized as a leading cause of death worldwide, but the risk of death is 2-3 times higher for individuals with diabetes. NLRP3 inflammasome activation is a leading pathway of vascular damage, and new treatment methods are needed to reduce NLRP3 inflammasome expression, along with a detailed understanding of how those treatments work. In a series of assays on human vascular endothelial cells that were exposed to high concentrations of free fatty acids (FFA) to induce a diabetes-like environment, we found a significant impact of cilostazol, a vasodilator widely used to treat blood flow problems and well-tolerated medication. To our knowledge, this study is the first to demonstrate the effects of cilostazol in primary human aortic endothelial cells. We found that cilostazol significantly reduced NLRP3 inflammasome activation, as well as the activity of other related and harmful factors, including oxidative stress, expression of NADPH oxidase 4 (NOX-4), thioredoxin-interacting protein (TxNIP), high mobility group box 1 (HMGB-1), interleukin 1b (IL-1b) and IL-18. Cilostazol also protected the functionality of sirtuin 1 (SIRT1), which serves to restrict NLRP3 inflammasome activity, when exposure to FFAs would have otherwise impaired its function. Thus, it appears that cilostazol's mechanism of action in reducing NLRP3 inflammasome activation is an indirect one; it protects SIRT1, which then allows SIRT1 to perform its regulatory job. Cilostazol has potential as an already-available, well-tolerated preventive medication that may alleviate some of the adverse vascular effects of living with diabetes. The findings of the present study lay the groundwork for further research on the potential of cilostazol as a safe and effective treatment against diabetic endothelial dysfunction and vacular disease.

Section: Discussionsupporting

confidence: 57%

Cilostazol ameliorates high free fatty acid (FFA)-induced activation of NLRP3 inflammasome in human vascular endothelial cells

Wang

Artificial Cells, Nanomedicine, and Biotechnology

et al. 2019

“…Cilostazol, a selective PDE-III inhibitor, acts as a vasodilator and antithrombotic antiplatelet agent, and it has been shown to promote lower triglyceride levels and increase HDL in patients with PAOD [22], to improve postprandial lipemia in patients with diabetes [13], to increase nitric oxide (NO) expression with a positive effect on apoptosis [23], to prevent thrombosis after stenting [24], and to have the ability to ameliorate atherosclerotic progression [25]. Cilostazol has also been reported to cause the accumulation of cAMP in VSMCs, resulting in the upregulation of antioncogenes p53 and p21 and hepatocyte growth factor [26].…”

Section: Discussionmentioning

confidence: 99%

Cilostazol inhibits hyperglucose-induced vascular smooth muscle cell dysfunction by modulating the RAGE/ERK/NF-κB signaling pathways

Hung

et al. 2019

J Biomed Sci

Background Increasing evidence suggests that high glucose (HG) causes abnormalities in endothelial and vascular smooth muscle cell function (VSMC) and contributes to atherosclerosis. Receptor for advanced glycation end-products (RAGE) has been linked to the pathogenesis of both the macrovascular and microvascular complications of diabetes. Cilostazol is used to treat diabetic vasculopathy by ameliorating HG-induced vascular dysfunction. Objectives In this study, we investigated whether the cilostazol suppression of HG-induced VSMC dysfunction is through RAGE signaling and its possible regulation mechanism. Method We investigated the effect of HG and cilostazol on RAGE signaling in A7r5 rat VSMCs. Aortic tissues of streptozotocin (STZ) diabetic mice were also collected. Results Aortic tissue samples from the diabetic mice exhibited a significantly decreased RAGE expression after cilostazol treatment. HG increased RAGE, focal adhesion kinase (FAK), matrix metalloproteinase-2 (MMP-2), intercellular cell adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1) expressions, and was accompanied with increased reactive oxygen species (ROS), cell proliferation, adhesion and migration. Cilostazol significantly reversed HG-induced RAGE, ROS, downstream gene expressions and cell functions. RAGE knockdown significantly reversed the expressions of HG-induced vasculopathy related gene expressions and cell functions. Cilostazol with RAGE knockdown had additive effects on downstream ERK/NF-κB signaling pathways, gene expressions and cell functions of A7r5 rat VSMCs in HG culture. Conclusions Both in vitro and in vivo experimental diabetes models showed novel signal transduction of cilostazol-mediated protection against HG-related VSMC dysfunction, and highlighted the involvement of RAGE signaling and downstream pathways.

“…EDHF plays a central role in the regulation of endothelial function for vasodilation and coordination of blood flow in the vasculature 10. The EDHF-mediated response is altered with aging, hypertension, diabetes, and hypoxia-reoxygenation injury 9,11,12,22. These alterations may either contribute to endothelial dysfunction or compensate for the loss of NO bioavailability, depending on the vascular bed 10.…”

Section: Discussionmentioning

confidence: 99%

“…EDHF plays an important role in the regulation of vascular tone, and impaired EDHF has been associated with endothelial dysfunction 10. Increasing evidence has shown that EDHF-mediated vasodilation decreases with aging, hypertension, and diabetes 9,11,12…”

Section: Introductionmentioning

confidence: 99%

<p>Exercise restores impaired endothelium-derived hyperpolarizing factor–mediated vasodilation in aged rat aortic arteries via the TRPV4-K<sub>Ca</sub>2.3 signaling complex</p>

Hai

Tan

et al. 2019

CIA

Background Aging leads to structural and functional changes in the vasculature characterized by arterial endothelial dysfunction and stiffening of large elastic arteries and is a predominant risk factor for cardiovascular disease, the leading cause of morbidity and mortality in modern societies. Although exercise reduces the risk of many age-related diseases, including cardiovascular disease, the mechanisms underlying the beneficial effects of exercise on age-related endothelial function fully elucidated. Purpose The present study explored the effects of exercise on the impaired endothelium-derived hyperpolarizing factor (EDHF)–mediated vasodilation in aged arteries and on the involvement of the transient receptor potential vanilloid 4 (TRPV4) channel and the small-conductance calcium-activated potassium (K Ca 2.3) channel signaling in this process. Methods Male Sprague-Dawley rats aged 19–21 months were randomly assigned to a sedentary group or to an exercise group. Two-month-old rats were used as young controls. Results We found that TRPV4 and K Ca 2.3 isolated from primary cultured rat aortic endothelial cells pulled each other down in co-immunoprecipitation assays, indicating that the two channels could physically interact. Using ex vivo functional arterial tension assays, we found that EDHF-mediated relaxation induced by acetylcholine or by the TRPV4 activator GSK1016790A was markedly decreased in aged rats compared with that in young rats and was significantly inhibited by TRPV4 or K Ca 2.3 blockers in both young and aged rats. However, exercise restored both the age-related and the TRPV4-mediated and K Ca 2.3-mediated EDHF responses. Conclusion These results suggest an important role for the TRPV4-K Ca 2.3 signaling undergirding the beneficial effect of exercise to ameliorate age-related arterial dysfunction.