Objective: To identify the principal circulating factors that modulate atheromatous matrix metalloproteinase (MMP) activity in response to diet and exercise.
Methods and Results: Apolipoprotein-E knock-out mice (n=56) with preexisting plaque, fed either Western diet (WD) or normal diet (ND), underwent either 10-week treadmill exercise or not. In vivo atheromatous MMP activity was visualized using molecular imaging with an MMP-2/9 activatable near-infrared-fluorescent probe. We measured atherosclerosis-related cytokines, lipid levels, visceral fat, and correlated these outcome measures to atheromatous MMP activity. Body weight, visceral fat, and plaque size were all higher in WD-fed animals than in ND-fed animals. Exercise training did not significantly affect these parameters in either WD-fed animals or ND-fed animals. However, atheromatous MMP activity was different: ND animals with and without exercise had similar low MMP activities, WD animals without exercise had high MMP activity, and WD animals with exercise had reduced levels of MMP activity, close to the levels of ND animals. Factor analysis and path analysis showed that soluble vascular cell adhesion molecule (sVCAM)-1 was directly positively related to atheromatous MMP activity. Adiponectin was indirectly negatively related to atheromatous MMP activity by way of sVCAM-1. Resistin was indirectly positively related to atheromatous MMP activity by way of sVCAM-1. In addition, visceral fat amount was indirectly positively associated with atheromatous MMP activity, by way of adiponectin reduction and resistin elevation.
Conclusion: Diet and exercise affects atheromatous MMP activity by modulating the systemic inflammatory milieu, with sVCAM-1, resistin, and adiponectin closely interacting with each other and with visceral fat.