Effects of Nicorandil on Inflammation, Apoptosis and Atherosclerotic Plaque Progression

Abstract

Nicorandil, a balanced vasodilator, is used in the second-line therapy of angina pectoris. In this study, we aimed to illuminate the effects of nicorandil on inflammation, apoptosis, and atherosclerotic plaque progression. Twenty-five LDL-R -/- mice were fed a high-fat diet for 14 weeks. After 6 weeks mice were randomly allocated to treatment with nicorandil (10 mg/kg/day) or tap water. Nicorandil treatment led to a more stable plaque phenotype, displaying an increased thickness of the fibrous cap (p = 0.014), a significant reduction in cholesterol clefts (p = 0.045), and enhanced smooth muscle cell content (p = 0.009). In endothelial cells nicorandil did not reduce the induction of adhesion molecules or proinflammatory cytokines. In H2O2 challenged endothelial cells, pretreatment with nicorandil significantly reduced the percentage of late apoptotic/necrotic cells (p = 0.016) and the ratio of apoptotic to living cells (p = 0.036). Atherosclerotic lesions of animals treated with nicorandil exhibited a significantly decreased content of cleaved caspase-3 (p = 0.034), lower numbers of apoptotic nuclei (p = 0.040), and reduced 8-oxogunanine staining (p = 0.039), demonstrating a stabilizing effect of nicorandil in established atherosclerotic lesions. We suggest that nicorandil has a positive effect on atherosclerotic plaque stabilization by reducing apoptosis.

Delivery of Nitric Oxide in the Cardiovascular System: Implications for Clinical Diagnosis and Therapy

“…The most widely used exogenous NO donors are organic nitrates (e.g., nitroglycerin, isosorbide dinitrates, and isosorbide mononitrate [24]); however, the features of unfavorable pharmacokinetics and the development of tolerance during chronic administration of organic nitrates might lead to increased synthesis of reactive oxygen species (ROS) and endothelial dysfunction [81][82][83]. To avoid the side effects of organic nitrates, inorganic nitrates or nitrites [84,85], nicorandil [86,87] and molsidomine [88] were gradually developed, showing promising effects to improve NO-mediated vasodilation and atherosclerotic plaque stability. Additionally, N-diazeniumdiolate (NONOate) has the unique advantage of having a high efficiency, which is capable of spontaneously releasing twice the amount of NO as a donor and has broad choices of half-life (2 s to 20 h) [17,89].…”

Immune-Associated Gene Signatures and Subtypes to Predict the Progression of Atherosclerotic Plaques Based on Machine Learning

“…The initiation of atherosclerosis involves endothelial activation, which recruits leukocytes to the arterial intima, in which they are linked to lipoprotein and its derivative, and thus accumulate in the layer ( Mushenkova et al, 2020 ). The long-term and slow progression of atherosclerosis involves persistent immune response, with intermittent acute activation episodes resulting from extravascular damage or immune activation at the site of infection or subclinical destruction of plaques ( Lenz et al, 2021 ). The single-cell immune landscape of the human atherosclerotic plaques has uncovered that innate and adaptive immune cells in plaques show associations with cerebrovascular events ( Fernandez et al, 2019 ).…”

An integrative analysis of single-cell and bulk transcriptome and bidirectional mendelian randomization analysis identified C1Q as a novel stimulated risk gene for Atherosclerosis

“…Several studies have demonstrated the involvement of immune cell infiltrations and pathways in atherosclerosis, highlighting their crucial role in atherosclerotic plaque progression ( 9 , 11 , 17 , 47 , 48 ). Figures 1E, F illustrates that in the PA group, endothelial cells (EC) and clusters of CD8+ T cells and fibroblasts constituted the top three cell clusters, whereas in the AC group, CD8+ T, CD4+ T, and macrophages were predominant.…”