Statins Show Anti-Atherosclerotic Effects by Improving Endothelial Cell Function in a Kawasaki Disease-like Vasculitis Mouse Model

Abstract

Kawasaki disease (KD) is an acute inflammatory syndrome of unknown etiology that is complicated by cardiovascular sequelae. Chronic inflammation (vasculitis) due to KD might cause vascular cellular senescence and vascular endothelial cell damage, and is a potential cause of atherosclerosis in young adults. This study examined the effect of KD and HMG-CoA inhibitors (statins) on vascular cellular senescence and vascular endothelial cells. Candida albicans water-soluble fraction (CAWS) was administered intraperitoneally to 5-week-old male apolipoprotein E-deficient (Apo E-/-) mice to induce KD-like vasculitis. The mice were then divided into three groups: control, CAWS, and CAWS+statin groups. Ten weeks after injection, the mice were sacrificed and whole aortic tissue specimens were collected. Endothelial nitric oxide synthase (eNOS) expression in the ascending aortic intima epithelium was evaluated using immunostaining. In addition, eNOS expression and levels of cellular senescence markers were measured in RNA and proteins extracted from whole aortic tissue. KD-like vasculitis impaired vascular endothelial cells that produce eNOS, which maintains vascular homeostasis, and promoted macrophage infiltration into the tissue. Statins also restored vascular endothelial cell function by promoting eNOS expression. Statins may be used to prevent secondary cardiovascular events during the chronic phase of KD.

PCSK9 attenuates efferocytosis in endothelial cells and promotes vascular aging

“… 57 Another study with ApoE -/- mice showed that statins promotes eNOS expression and restores vascular endothelial cell function. 58 In summary, anti-aging effects of stains are mainly based on downregulation of oxidative stress and pro-inflammatory response while upregulation of eNOS expression that leads to enhanced NO bioavailability and improved endothelial function. Therefore, to determine whether the benefit effects of statins are directly related to PSCK9 inhibition, immunofluorescent staining was performed for the aging markers (e.g.…”

Statins—Beyond Their Use in Hypercholesterolemia: Focus on the Pediatric Population

“…In this context, it is important to understand the mechanisms beyond the positive impact on inflammation and coronary artery abnormalities. In a murine study, atorvastatin demonstrated anti-atherosclerotic effects by enhancing the function of endothelial cells in artificially induced Kawasaki-like vasculitis [42]. Motoji et al showed that the use of statins may be able to prevent the cardiovascular events associated with Kawasaki disease by stimulating the expression of endothelial nitric oxide synthase (eNOS), which restored the function of endothelial cells [42].…”

Statins in Chronic Kidney Disease—Effects on Atherosclerosis and Cellular Senescence

“…Using vascular cells as an example, it has been shown that cellular senescence can be triggered by chronic inflammation. This ultimately leads to endothelial dysfunction, which promotes atherosclerosis [ 54 ] and other CVDs [ 55 ].…”

“…Motoji et al [ 54 ] conducted a study in mice to test how vasculitis and statins affect cellular senescence and vascular endothelial cells. The study used atorvastatin at a dose of 10 mg/kg/day.…”

“…Statin use was not shown to inhibit vascular cellular senescence induced by vascular inflammation. However, a study revealed that statins affecting the phosphatidylinositol 3-kinases/protein kinase B/endothelial nitric oxide synthase (PI3K/Akt/eNOS) and Ras homolog family member 1/rho-associated, coiled-coil-containing protein kinase 1 (Rho/ROCK) pathways increased Akt and eNOS activity, thereby improving endothelial cell function [ 54 ].…”