Abstract P211: Intra-abdominal Lipectomy Normalizes Arterial Stiffness and Blood Pressure via Reduction in 20-HETE

Increased intra-abdominal (visceral) adipose tissue is a key feature of the metabolic syndrome affecting over 30% of the U.S. population. Expansion of visceral adipose tissue is linked to the development of hypertension and is a risk factor for cardiovascular disease that can ultimately lead to end-organ damage. While reduction in visceral adipose tissue volume offers cardioprotective effects, the cardiovascular mechanisms behind these beneficial effects remain unclear. In this study, we removed ~90% of visceral adipose tissue (=~5% body weight) by intra-abdominal lipectomy and assessed large arterial stiffness, large artery structural matrix components, and blood pressure in a metabolic syndrome rat model (JCR:LA-cp, JCR). Large artery stiffness was significantly elevated in JCR vs. normal (Sprague Dawley, SD) rats (75±2% JCR vs. SD (carotid)) with a concomitant significant increase in MMP12-dependent elastin degradation (3-6 fold vs. SD). Intra-abdominal lipectomy normalized large artery stiffness, blocked MMP12 activation and reduced elastin degradation in JCR animals (~75% (carotid) vs. untreated JCR). Likewise, hypertension in JCR animals was significantly attenuated by intra-abdominal lipectomy (MABP=156±3 mmHg JCR vs. 90±6 mmHg SD vs. 132±4 mmHg JCR+lipectomy). 20-hydroxyeicosatetraeonic acid (20-HETE), an arachidonic acid metabolite known to be a potent vasoconstrictor in resistance arteries, was significantly elevated in the visceral adipose tissue of JCR rats (~6 fold vs. SD). Intra-abdominal lipectomy normalized 20-HETE levels in JCR rats. Like intra-abdominal lipectomy, 20-HETE antagonists restored large artery elasticity, blocked MMP12 activation and elastin degradation, and significantly decreased blood pressure (125±3 mmHg JCR+20-HETE antagonists) in JCR rats. Thus, 20-HETE may be an important adipokine that mediates the adverse effects of expanded visceral fat volume in the metabolic syndrome and its inhibition may provide a pharmacological approach for the management of central obesity-driven large artery stiffness and hypertension.

Abstract 040: Comparison of Effects of Reux en Y Gastric Bypass and Intra-abdominal Lipectomy on Cardiovascular Function in the Metabolic Syndrome

Central (visceral) obesity is a key feature of the metabolic syndrome and an independent predictor of cardiovascular disease. Reux en Y gastric bypass (RnY) has been shown to offer protection against cardiovascular disease, but residual risk remains. It is also unknown whether the cardiovascular benefit is a consequence of a decrease in visceral (intra-abdominal) adipose tissue or of other factors. In this study, we compared the effects of RnY vs. removal of 90% of visceral adipose tissue (=5% body weight) by intra-abdominal lipectomy on cardiac function (echocardiography), macrovascular function (carotid artery stiffness) and microvascular function (coronary artery endothelium-dependent vasorelaxation) in a metabolic syndrome rat model (JCR:LA-cp, JCR). Cardiac output (CO) and ejection fraction (EF) were significantly decreased in JCR vs. normal (Sprague-Dawley, SD) rats (CO=50±5%, EF=45±2% of normal), and were significantly improved by both RnY and intra-abdominal lipectomy (CO=75±6%, EF=82±2% and CO=80±3%, EF=90±2% of normal, respectively). Likewise, acetylcholine-dependent coronary artery vasorelaxation was impaired in JCR rats (50±1% of normal), and was significantly improved by both RnY and intra-abdominal lipectomy (98±2% and 98±3% of normal, respectively). Carotid artery stiffness was significantly increased in JCR rats (~2 fold vs. SD), and was normalized by intra-abdominal lipectomy (to equal SD), but not by RnY (~2 fold vs. SD). Intra-abdominal lipectomy but not RnY also decreased cardiac and vascular elastin degradation in JCR rats (Lipectomy: ~50% (heart), ~75% (carotid); RnY: ~15% (heart), ~5% (carotid) vs. untreated JCR, respectively), concomitant with a decrease in matrix metalloproteinase 12 (MMP12), a major elastase, activation (~50% (heart), ~75% (carotid), ~87% (visceral fat), ~75% (circulating) vs. untreated JCR) and in 20-hydroxyeicosatetraeonic acid (20-HETE) levels (~4 (heart), ~7 (carotid), ~4 (visceral fat), ~4 (circulating) fold vs. untreated JCR). Thus, our data indicate that intra-abdominal adipose tissue itself is a source of factors that may be important negative regulators of micro- and macrovascular and cardiac function, but are not eliminated by RnY.