Kazuyuki Ogawa1, Takahiro Ueno2, Tadao Iwasaki3, Takeshi Kujiraoka3, Mitsuaki Ishihara3, Satoshi Kunimoto4, Tadateru Takayama4, Takashi Kanai4, Atsushi Hirayama4, Hiroaki Hattori3. 1. Advanced Medical Technology and Development Division, BML Inc., Saitama 350-1101, Japan. Electronic address: ogawa-k@bml.co.jp. 2. Division of Nephrology, Hypertension and Endocrinology, Department of Medicine, Nihon University School of Medicine, Tokyo 173-8610, Japan. 3. Advanced Medical Technology and Development Division, BML Inc., Saitama 350-1101, Japan. 4. Division of Cardiology, Department of Medicine, Nihon University School of Medicine, Tokyo 173-8610, Japan.
Abstract
OBJECTIVE: Sortilin is involved multilaterally in the development of atherosclerosis. Here, we examine the release of soluble sortilin (sSortilin) from platelets and assess the association between circulating levels of sSoritlin and atherothrombosis such as coronary artery disease (CAD). METHODS AND RESULTS: sSortilin levels measured in healthy subjects were higher in serum than in plasma (38.4 ± 8.7 vs. 15.8 ± 2.9 ng/mL; p < 0.0001). Platelets were shown to contain both membrane-bound sortilin and its soluble form lacking the cytoplasmic tail. Stimulation of platelet-rich plasma with collagen induced sSortilin release concomitantly with platelet aggregation, and the release was suppressed by aspirin. In clinical evaluation, plasma sSortilin was detected at significantly higher levels in cardiovascular risk patients with hypertension, dyslipidemia, and/or diabetes without CAD (non-CAD, 18.7 ± 3.3 ng/mL) than in patients with CAD under aspirin therapy (17.1 ± 3.6 ng/mL; p < 0.01) or in healthy controls (16.8 ± 2.9 ng/mL; p < 0.01). In these patients, plasma sSortilin levels were significantly correlated with platelet counts (rs = 0.33; p = 0.0085) and showed significant positive associations with cardiovascular risk factors: low-density lipoprotein cholesterol (rs = 0.37; p = 0.0023), triglycerides (rs = 0.28; p = 0.023), and serum uric acid (rs = 0.30; p = 0.017) in non-CAD, and γ-glutamyltransferase (rs = 0.43; p = 0.020) and high-sensitivity C-reactive protein (rs = 0.33, p = 0.0022) in CAD. CONCLUSION: Elevated plasma sSortilin levels may be associated with in vivo platelet activation and could be a risk factor for atherothrombosis.
OBJECTIVE:Sortilin is involved multilaterally in the development of atherosclerosis. Here, we examine the release of soluble sortilin (sSortilin) from platelets and assess the association between circulating levels of sSoritlin and atherothrombosis such as coronary artery disease (CAD). METHODS AND RESULTS:sSortilin levels measured in healthy subjects were higher in serum than in plasma (38.4 ± 8.7 vs. 15.8 ± 2.9 ng/mL; p < 0.0001). Platelets were shown to contain both membrane-bound sortilin and its soluble form lacking the cytoplasmic tail. Stimulation of platelet-rich plasma with collagen induced sSortilin release concomitantly with platelet aggregation, and the release was suppressed by aspirin. In clinical evaluation, plasma sSortilin was detected at significantly higher levels in cardiovascular risk patients with hypertension, dyslipidemia, and/or diabetes without CAD (non-CAD, 18.7 ± 3.3 ng/mL) than in patients with CAD under aspirin therapy (17.1 ± 3.6 ng/mL; p < 0.01) or in healthy controls (16.8 ± 2.9 ng/mL; p < 0.01). In these patients, plasma sSortilin levels were significantly correlated with platelet counts (rs = 0.33; p = 0.0085) and showed significant positive associations with cardiovascular risk factors: low-density lipoprotein cholesterol (rs = 0.37; p = 0.0023), triglycerides (rs = 0.28; p = 0.023), and serum uric acid (rs = 0.30; p = 0.017) in non-CAD, and γ-glutamyltransferase (rs = 0.43; p = 0.020) and high-sensitivity C-reactive protein (rs = 0.33, p = 0.0022) in CAD. CONCLUSION: Elevated plasma sSortilin levels may be associated with in vivo platelet activation and could be a risk factor for atherothrombosis.