Abstract 10731: Mmp14-dependent Paradoxical Link Between Obesity and Atherosclerosis
Both high and low BMIs are associated with the increased risk of coronary heart disease (CHD); however, the molecular mechanism that underlies the U-curve association between BMI and CHD remains unknown. MMP14, also known as MT1-MMP, is the major membrane-type collagenase that regulates fat mass and function in vivo. The loss of Mmp14 renders mice lipodystrophic, whereas Mmp14 heterozygous mice are protected from high fat diet (HFD)-induced obesity. Moreover, macrophage MMP14 regulates collagen content in atherosclerotic lesions. We hypothesized that Mmp14 haploinsufficiency should protect mice from diet-induced atherosclerosis.
Method: We crossed Mmp14 heterozygous mice (in C57/BL6 >10 generations) to ApoE-null mice (Jackson) and fed the offspring [HT-Mmp14(+/-)/ApoE(-/-), and WT- Mmp14(+/+)/ApoE(-/-)] atherogenic Western Diet (D12109) for 12 weeks since age 8 weeks (male, N=9 each). We defined the relationship between obesity and atherogenesis by assessing atherosclerosis with Oil-Red-O en face staining of whole arterial trees/aorta, vascular collagen content with Sirius red staining, epididymal white adipose tissue (eWAT) gene expression with qPCR, and statistical analysis with ANCOVA.
Results: HT mice displayed 40% reduction of fat mass relative to WT on Western Diet and decreased fasting insulin level (HT 3.8, WT 11.8 mU/L). Fasting LDL levels were similarly elevated in both groups (HT 349 ± 71, WT 359 ± 78 mg/dL). Contrary to our hypothesis, HT mice displayed increased plaque area particularly in abdominal aorta (HT 7.9 ± 0.8 %total, WT 1.5 ± 0.4, p=0.0008). Sirius red staining demonstrates increased collagen deposition and thickened vascular walls in HT mice. In both genotypes, MMP14 expression in eWAT positively correlates with fat mass (HT, r = 0.6, WT 0.7) and negatively correlates with the degree of atherosclerosis (HT, r = -0.65 HT, WT -0.75). ANCOVA suggests that Mmp14 allele dose associates with increased fat mass (p=0.0075) and decreased atherosclerosis (p=0.01). Together, these results suggest that MMP14-dependent pathway may act as the major modifier of the paradoxical link between fat mass and the risk of atherosclerosis.
- © 2013 by American Heart Association, Inc.