Abstract 15533: Impact of Proteinase 3 and Insulin Growth Factor BP-3 Proteolysis in Obesity-Induced Cardiometabolic Risk
Obesity is a major risk factor for CMR. A recent endocrine paradigm suggests that visceral fat secretes pro-inflammatory and pro-atherogenic TNF-α, CRP, and IL-6, resulting in chronic systemic inflammation and CMR.
We found that IGFBP-3 inhibits production of pro-inflammatory cytokines as well as inflammatory NF-κB activity through the newly identified IGFBP-3 receptor (IGFBP-3R), thereby attenuating CMR. Further in vitro study showed IGFBP-3 inhibits TNF-a, CRP and NF-kB activity in human aortic endothelial cells (HAECs), subsequently suppressing monocyte adhesion through the IGFBP-3R. Also, obese individuals demonstrate reduced total IGFBP-3 and increased proteolytic fragments of IGFBP-3 in circulation compared to non-obese counterparts. Based on these findings, we tested the hypothesis that obesity-associated protease(s) contribute to increased IGFBP-3 proteolysis in circulation and abrogate anti-inflammatory and anti-atherogenic actions of the IGFBP-3/IGFBP-3R cascade in CV cells, thereby increasing CMR. To identify a specific protease responsible for obesity-induced IGFBP-3 proteolysis, we investigated neutrophil serine protease, proteinase 3 (PR3), since PR3 is activated in obesity.
In vitro proteolysis assays showed that IGFBP-3 is proteolyzed by PR3 while PR3 inhibitor, α–1-antitrypsin completely inhibits PR3-induced IGFBP-3 proteolysis. To identify functional significance of PR3 in obesity-induced IGFBP-3 proteolysis and its correlation with obesity, we analyzed 34 serum samples of lean (n=14), overweight (n=14) and obese (n=6) women. An increase in proteolyzed IGFBP-3 as well as PR3 was observed in overweight and obese individuals when compared to lean counterparts. Further, IGFBP-3 proteolysis is positively correlated with PR3 levels, BMI and HOMA-IR. These data suggest that systemic inflammation in obesity increases PR3 activity, significantly increasing IGFBP-3 proteolysis and abrogates anti-inflammatory, anti-atherogenic actions of IGFBP-3, resulting in increased CMR. The complete characterization of the underlying mechanism and functional significance of the PR3-IGFBP-3/IGFBP-3R cascade in obesity will help identify diagnostic and therapeutic potential of PR3 inhibitor and IGFBP-3 for CMR.
- © 2013 by American Heart Association, Inc.