Elevated Plasma Levels of MMP-12 Are Associated With Atherosclerotic Burden and Symptomatic Cardiovascular Disease in Subjects With Type 2 Diabetes

Abstract

Objective— Matrix metalloproteinases (MMPs) degrade extracellular matrix proteins and play important roles in development and tissue repair. They have also been shown to have both protective and pathogenic effects in atherosclerosis, and experimental studies have suggested that MMP-12 contributes to plaque growth and destabilization. The objective of this study was to investigate the associations between circulating MMPs, atherosclerosis burden, and incidence of cardiovascular disease with a particular focus on type 2 diabetes mellitus. Approach and Results— Plasma levels of MMP-1, -3, -7, -10, and -12 were analyzed by the Proximity Extension Assay technology in 1500 subjects participating in the SUMMIT (surrogate markers for micro- and macrovascular hard end points for innovative diabetes tools) study, 384 incident coronary cases, and 409 matched controls in the Malmö Diet and Cancer study and in 205 carotid endarterectomy patients. Plasma MMP-7 and -12 were higher in subjects with type 2 diabetes mellitus, increased with age and impaired renal function, and was independently associated with prevalent cardiovascular disease, atherosclerotic burden (as assessed by carotid intima-media thickness and ankle-brachial pressure index), arterial stiffness, and plaque inflammation. Baseline MMP-7 and -12 levels were increased in Malmö Diet and Cancer subjects who had a coronary event during follow-up. Conclusions— The plasma level of MMP-7 and -12 are elevated in type 2 diabetes mellitus, associated with more severe atherosclerosis and an increased incidence of coronary events. These observations provide clinical support to previous experimental studies, demonstrating a role for these MMPs in plaque development, and suggest that they are potential biomarkers of atherosclerosis burden and cardiovascular disease risk.

Impact of Diabetes Mellitus

“…The same group then continued to show that plasma levels of the matrix metalloproteinases 7 and 12 were elevated in type 2 diabetics and were associated with increased incidence of atherosclerosis and cardiovascular disease. 26 …”

Matrix metalloproteinase-3 gene promoter polymorphisms: A potential risk factor for pelvic organ prolapse

“…However, it may be favorable in other conditions, such as POP (24). In a recent study by Goncalves et al , it was shown that ‘high plasma levels of MMP-3 were associated with lower plaque elastin content’ (32). Therefore, a higher MMP-3 gene expression potentially decreases elastin concentrations in human body tissues, such as pelvic floor supporting structures (i.e., ligaments and fascia).…”

Atherosclerotic Plaque Rupture

“…25 Consistent with the role of matrix metalloproteinases in destabilizing atherosclerotic plaques, elevated plasma levels of matrix metalloproteinase-12, which can degrade elastin, fibronectin, laminin, and type IV collagen, correlate with an increased rate of coronary events in patients with type 2 diabetes mellitus. 26 However, there are also descriptions of plasma biomarkers that correlate with a more stable fibrous plaque phenotype and a lower incidence of cardiovascular events. Rattik et al 27 describe smooth muscle cell growth factors (eg, heparin-binding epidermal growth factor) as such markers.…”