Serum MMP‐3 and its Association with Large Artery Stiffness

Abstract

Large artery stiffness is an independent predictor of cardiovascular disease (CVD) and all‐cause mortality. Stiffening of the large arteries (e.g., the aorta) is characterized by a marked reduction in the elastin‐collagen ratio in the extracellular matrix (ECM) of the arterial wall, and is largely the result of fatigue and fragmentation of ECM components due to cyclic stress. Matrix metalloproteinases (MMPs), a family of zinc‐dependent endopeptidases, may be important in the progression of arterial stiffness due to their involvement in ECM homeostasis and arterial wall remodeling. MMP‐3 may be of particular importance in arterial wall remodeling due to its ability to degrade numerous constituents of the arterial ECM, such as elastin and collagen. Previous studies have examined the effects of MMP‐3 genotype and expression on arterial wall stiffness in different disease populations; however, none have examined the association between MMP‐3 expression and large artery stiffness in a population of healthy young adults. Thus, the purpose of this study was to examine the association between serum MMP‐3 and carotid‐femoral pulse wave velocity (cfPWV), a non‐invasive measure of large artery stiffness, in a sample of healthy young adults. It is expected that individuals with higher serum MMP‐3 levels will present with larger cfPWVs. 156 participants (n = 68 males) aged 20–25 years were recruited as part of the Niagara Longitudinal Heart Study (NLHS), and all participants were free of any clinically diagnosed CVD. cfPWV (m/s) was determined using applanation tonometry as a non‐invasive surrogate of large artery stiffness. Serum MMP‐3 concentrations (pg/mL) were measured using standard ELISA techniques. Linear regression analyses were used to investigate the cross‐sectional association between serum MMP‐3 and cfPWV. Analyses were adjusted for age, sex, mean arterial pressure (MAP), body mass index (BMI), and smoking status. Data on cfPWV and MMP‐3 were available on 139 participants (n = 63 males), and were subsequently used in analysis. After adjustment for age, sex, MAP, BMI, and smoking status, serum MMP‐3 was significantly and positively associated with cfPWV (p = 0.038). cfPWV was also significantly and positively associated with MAP and smoking status (both p < 0.001), but not age (p = 0.336). The association between cfPWV and both sex and BMI showed a positive trend, but only reached borderline significance (p = 0.059 and p = 0.054, respectively). Together, MAP, smoking status and serum MMP‐3 predicted 22% of the variation in cfPWV (adjusted R2 = 0.220, p < 0.001). These data suggest that greater serum MMP‐3 levels are associated with larger cfPWVs and thus, greater large artery stiffness. Physiologic MMP‐3 levels function to maintain ECM homeostasis; however, greater MMP‐3 levels may exacerbate ECM degradation and contribute to stiffening of the large arteries. Future research should examine the potential functional role of MMP‐3 in CVD progression.Support or Funding InformationThe NLHS is funded by the Canadian Institute of Health Research (CIHR #363774 and #399332). KSD is funded by CIHR Doctoral Research Award—Frederick Banting and Charles Best Canada Graduate scholarship (RFN #167014). ARRM is supported by the Ontario Graduate Scholarship program