AUTHOR=Liu Bingli , Su Liping , Loo Sze Jie , Gao Yu , Khin Ester , Kong Xiaocen , Dalan Rinkoo , Su Xiaofei , Lee Kok-Onn , Ma Jianhua , Ye Lei 

TITLE=Matrix metallopeptidase 9 contributes to the beginning of plaque and is a potential biomarker for the early identification of atherosclerosis in asymptomatic patients with diabetes

JOURNAL=Frontiers in Endocrinology

VOLUME=15

YEAR=2024

URL=https://www.frontiersin.org/journals/endocrinology/articles/10.3389/fendo.2024.1369369

DOI=10.3389/fendo.2024.1369369

ISSN=1664-2392

ABSTRACT=<sec><title>Aims</title><p>To determine the roles of matrix metallopeptidase-9 (MMP9) on human coronary artery smooth muscle cells (HCASMCs) <italic>in vitro</italic>, early beginning of atherosclerosis <italic>in vivo</italic> in diabetic mice, and drug naïve patients with diabetes.</p></sec><sec><title>Methods</title><p>Active human MMP9 (act-hMMP9) was added to HCASMCs and the expressions of MCP-1, ICAM-1, and VCAM-1 were measured. Act-hMMP9 (n=16) or placebo (n=15) was administered to diabetic KK.Cg-<italic>A<sup>y</sup></italic>/J (KK) mice. Carotid artery inflammation and atherosclerosis measurements were made at 2 and 10 weeks after treatment. An observational study of newly diagnosed drug naïve patients with type 2 diabetes mellitus (T2DM n=234) and healthy matched controls (n=41) was performed and patients had ultrasound of carotid arteries and some had coronary computed tomography angiogram for the assessment of atherosclerosis. Serum MMP9 was measured and its correlation with carotid artery or coronary artery plaques was determined.</p></sec><sec><title>Results</title><p><italic>In vitro</italic>, act-hMMP9 increased gene and protein expressions of MCP-1, ICAM-1, VCAM-1, and enhanced macrophage adhesion. Exogenous act-hMMP9 increased inflammation and initiated atherosclerosis in KK mice at 2 and 10 weeks: increased vessel wall thickness, lipid accumulation, and Galectin-3+ macrophage infiltration into the carotid arteries. In newly diagnosed T2DM patients, serum MMP9 correlated with carotid artery plaque size with a possible threshold cutoff point. In addition, serum MMP9 correlated with number of mixed plaques and grade of lumen stenosis in coronary arteries of patients with drug naïve T2DM.</p></sec><sec><title>Conclusion</title><p>MMP9 may contribute to the initiation of atherosclerosis and may be a potential biomarker for the early identification of atherosclerosis in patients with diabetes.</p></sec><sec><title>Clinical trial registration</title><p><uri xlink:href="https://www.clinicaltrials.gov" xmlns:xlink="http://www.w3.org/1999/xlink">https://clinicaltrials.gov</uri>, identifier NCT04424706.</p></sec>