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

Abstract

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.

Effect of cilostazol on carotid plaque volume measured by three‐dimensional ultrasonography in patients with type 2 diabetes: The FANCY study

“…A recent T A B L E 2 Changes in carotid ultrasonography findings, ankle-brachial index, and microcirculation after cilostazol or aspirin treatment study showed the potential of cilostazol as an effective treatment for diabetic endothelial dysfunction and vascular disease by reducing inflammasome activity. 42 These data support the contention that improvement in vascular function can be expected after cilostazol treatment.…”

“…The PORH was slightly increased in the CTZ group, while it exhibited a decreasing tendency in the ASA group, leading to a borderline significant difference between the two groups. A recent study showed the potential of cilostazol as an effective treatment for diabetic endothelial dysfunction and vascular disease by reducing inflammasome activity 42 . These data support the contention that improvement in vascular function can be expected after cilostazol treatment.…”

NLRP3 inflammasome in endothelial dysfunction

“…Cilostazol significantly reduces NLRP3 inflammasome activation and the activity of NOX4, TXNIP, HMGB1, IL-1β, and IL-18 in HAECs induced with FFA. Cilostazol also protected the function of SIRT1, which serves to limit the activity of NLRP3 inflammasome 102 .…”

The Emerging Role of TXNIP in Ischemic and Cardiovascular Diseases; A Novel Marker and Therapeutic Target

“…Interestingly, the deletion of endothelial TXNIP in mice or in vivo anti-TXNIP treatment protects from oxidative stress and NLRP3 inflammasome activation [13,21]. Metformin or other compounds are also used to lower TXNIP aortic levels in vivo or endothelial levels in vitro in order to restrain NLRP3 activation and protect from endothelial dysfunction and cardiovascular risk factors [60,67,87,[91][92][93][94][95][96][97][98][99][100][101]. The regulation of the NLRP3 inflammasome by the TRX-TXNIP complex is believed to be controlled by Nrf2 and AMPK [60,[102][103][104]106,107].…”