Cytokine Response to Diet and Exercise Affects Atheromatous Matrix Metalloproteinase-2/9 Activity in Mice.

BACKGROUND: The aim of this study is 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 (ApoE-/-) mice (n=56) with pre-existing plaque, fed either a Western diet (WD) or normal diet (ND), underwent either 10 weeks of treadmill exercise or had no treatment. Atheromatous MMP activity was visualized using molecular imaging with a MMP-2/9 activatable near-infrared fluorescent (NIRF) probe. Exercise did not significantly reduce body weight, visceral fat, and plaque size in either WD-fed animals or ND-fed animals. However, atheromatous MMP-activity was different; ND animals that did or did not exercise had similarly low MMP activities, WD animals that did not exercise had high MMP activity, and WD animals that did 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 correlated 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. Visceral fat amount was indirectly positively associated with atheromatous MMP activity, by way of adiponectin reduction and resistin elevation. MMP-2/9 imaging of additional mice (n=18) supported the diet/exercise-related anti-atherosclerotic roles for sVCAM-1. CONCLUSIONS: Diet and exercise affect atheromatous MMP activity by modulating the systemic inflammatory milieu, with sVCAM-1, resistin, and adiponectin closely interacting with each other and with visceral fat.

Atorvastatin and clopidogrel interfere with photosensitization in vitro.

Photodynamic therapy (PDT) has been used to eliminate undesired cells by using a combination of photosensitizers and light illumination to generate reactive oxygen species. There is great interest in applying PDT to atherosclerosis; preferential destruction of pro-inflammatory macrophages in atheromata might attenuate plaque growth or rupture-prone vulnerability. Here, we report on a previously unknown interaction between cardiovascular drugs that are commonly prescribed for atherosclerosis patients and the cytolytic effects of photodynamic therapy using Cathepsin B activatable photosensitizer L-SR15 on murine macrophage Raw 264.7 cells in culture. Atorvastatin and clopidogrel significantly interfered with in vitro photosensitization effect while aspirin did this to a lesser extent; these drugs did not change the efficiency of cellular uptake of L-SR15 after in vitro photosensitization. A photosensitization interference effect of atorvastatin and clopidogrel was also observed when using a conventional photosensitizer free Ce6 or NCI-H1299 cancer cells. Considering the clinical implications of PDT, our study merits further investigation in clinical settings as well as in animal models.

Early treadmill training promotes motor function after hemorrhagic stroke in rats.

Rehabilitation after a stroke is very important because it has beneficial effects on brain function, including the promotion of plasticity. However, an optimal time window for rehabilitation interventions after hemorrhagic stroke has not been clearly defined. The aim of this study was to determine whether early exercise training initiated 24h after an intracerebral hemorrhage (ICH) might enhance neurologic recovery more than exercise initiated 1 week after ICH without hematoma expansion and edema volume increase. We subjected adult male Sprague-Dawley rats to experimental ICH by the intrastriatal administration of bacterial collagenase. The rats were randomly divided into the following 2 groups: early training group (treadmill exercise started 24h post-ICH; n=18) and late training group (treadmill exercise started 1-week post-ICH; n=18). Two weeks after surgery we performed neurologic tests (rota-rod, modified limb-placing, and adhesive-dot removal tests), and measured hematoma volumes and brain water content. In the late training group, compared with the pre-ICH performance on the rota-rod test (98.3+/-69.4s), the animals had significantly worse performance after the post-ICH rehabilitation (40.5+/-52.6s; p<0.01, paired t-test). In the early training group however, the motor performance after the post-ICH rehabilitation (56.4+/-73.5s) was not significantly different from the baseline pre-ICH performance (79.8+/-33.9s; p=0.24). There were no significant differences between the two groups with respect to the other neurologic tests. Early exercise did not increase hematoma size or brain water content. Early treadmill training could be performed safely, and enhanced motor recovery in a rat model of ICH. Further studies are required to translate the results into clinical significance.