Abstract
Arterial stiffening is a risk factor for cardiovascular morbidity. Recent studies have shown that lysosomal ceramide contributed to the phenotype change and exosome secretion in arterial smooth muscle cells (SMCs) during the development of arterial medial calcification. The present study was designed to investigate whether lysosomal ceramide produced from acid sphingomyelinase (ASM) contributes to arterial stiffening in diet-induced obesity. It was found that in a diet-induced mouse model of obesity by feeding mice high fat diet (HF), arterial stiffness as measured in vivo using a high-resolution Doppler ultrasound imaging was significantly enhanced in mice with a transgene of ASM (its mouse gene code is Smpd1), namely, Smpd1trg/SMCre mice as compared to their wild type littermates (WT/WT). This obesity-induced enhancement of arterial stiffening was further strengthened by administration of high sucrose water (30%). Smpd1trg/SMCre mice on the HF diet or HF diet with high sucrose water (HFHS) showed significantly increased glucose levels as compared to WT/WT without significant difference in the body weight. By Masson Trichrome staining, we observed markedly increased collagen deposition in Smpd1trg/SMCre mice treated with HF diet, which was further increased in HFHS group of mice compared to WT/WT. Furthermore, Smpd1trg/SMCre mice treated with HF or HFHS were shown to have significant increase in the expression of exosome markers such as CD63 and annexin-II (AnX2) in the coronary arterial wall as compared to WT/WT mice. In the plasma of Smpd1trg/SMCre mice, the number of exosomes also significantly increased as compared to WT/WT mice either on normal, HF or HFHS diet. All these data indicate that a transgene of ASM in Smpd1trg/SMCre mice leads to increased glucose and collagen levels associated with augmented exosomes secretion that may contribute to the enhancement of arterial stiffening during diet-induced obesity.
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