Abstract 122: 20-HETE Antagonists Normalize Large Artery Stiffness and Systolic Blood Pressure in Metabolic Syndrome

Abstract

Large artery stiffness is a causal factor in development of systolic hypertension. 20-hydroxyeicosatetraeonic acid (20-HETE), a cytochrome CYP450-derived arachidonic acid metabolite, is known to be elevated in resistance arteries in hypertensive animal models and in obesity in humans, but the role of 20-HETE in regulation of large artery remodeling in metabolic syndrome has not been investigated. Unlike normal (Sprague-Dawley (SD)) rats, large arteries (aorta, carotid and >100μM mesenteric arteries) of metabolic syndrome rats (JCR:LA-cp, JCR) express CYP4A and 4F, CYP450s which make 20-HETE in rats (2-fold increase vs. SD). Consequently, 20-HETE production is elevated in large arteries of JCR rats. We hypothesized that this elevated 20-HETE increases matrix metalloproteinase 12 (MMP12, an elastase) activation leading to increased degradation of elastin, increased large artery stiffness and increased systolic blood pressure. A 3-4 fold increase in 20-HETE production in large arteries of JCR vs. SD rats correlated with increased elastin degradation (3-6 fold) and increased arterial stiffness (~75%). 20-HETE antagonists blocked elastin degradation in JCR rats concomitant with blocking MMP12 activation. Importantly, 20-HETE antagonists and MMP12 inhibition (pharmacological and MMP12-shRNA-Lnv) significantly decreased (~60% vs. untreated JCR) large artery stiffness in JCR rats. 20-HETE antagonists also decreased systolic (182±3 mmHg JCR, 145±3 mmHg JCR+20-HETE antagonists) but not diastolic (125±4 mmHg JCR, 124±4 mmHg JCR+20-HETE antagonists) blood pressure in JCR rats. Whereas diastolic pressure was fully angiotensin II (Ang II)-dependent, systolic pressure was only partially Ang II-dependent, and large artery stiffness in JCR rats was Ang II-independent. These results suggest that 20-HETE-dependent regulation of systolic blood pressure may be a unique feature of metabolic syndrome related to high CYP4A/4F expression and resultant high 20-HETE production in large conduit arterial stiffness, which is a primary determinant of systolic blood pressure. These findings may have implications for management of systolic hypertension in patients with metabolic syndrome.