20‐HETE Increases Large Artery Stiffness and Systolic Blood Pressure in Metabolic Syndrome

Abstract

Hypertension is a risk factor that is associated with the metabolic syndrome. Large artery stiffness, which is in part a result of elastin degradation, plays a causal role in the development of isolated systolic hypertension, which is especially common in the elderly. Levels of 20‐hydroxyeicosatetraeonic acid (20‐HETE), a cytochrome (CYP)‐derived arachidonic acid metabolite, are greatly elevated in hypertensive animal models and loosely associated with obesity in humans, but 20‐HETE's role in the regulation of arterial stiffness in the metabolic syndrome has not been investigated. We hypothesized that elevated 20‐HETE in metabolic syndrome increases matrix metalloproteinase 12 (MMP12) activation leading to increased elastin degradation, increased large artery stiffness and increased systolic blood pressure. Our study shows that elastin degradation was increased ~4 fold in large arteries of metabolic syndrome rats (JCR:LA‐cp, JCR) vs. Sprague‐Dawley (SD) control rats. This correlated with increased large artery stiffness (75%±2% JCR vs. SD). 20‐SOLA (2,5,8,11,14,17‐hexaoxanonadecan‐19‐yl 20‐hydroxyicosa‐6(Z),15(Z)‐dienoate) a 20‐HETE antagonist, blocked elastin degradation in JCR rats, concomitant with decreasing MMP12 activation. Importantly, both 20‐SOLA and MMP12 inhibition (pharmacological and MMP12‐shRNA‐Lnv) decreased large artery stiffness in JCR rats (3%±2% JCR+20‐SOLA vs. SD, 18%±4.3% JCR+MMP12 inhibition vs. SD). 20‐SOLA and MMP12 inhibition also decreased systolic but not diastolic blood pressure in JCR rats (113±6 mmHg SD, 159±4 mmHg JCR, 130±4 mmHg JCR+20‐SOLA, 139±5 JCR+MMP12 mmHg inhibition). These data suggest that a portion of the systolic but not diastolic component of hypertension in the metabolic syndrome JCR rats is 20‐HETE‐sensitive and dependent on large artery stiffness/compliance. The source(s) of 20‐HETE and MMP12 responsible for increased elastin degradation and large artery stiffness are likewise unknown. Intra‐abdominal lipectomy (removal of visceral fat=5% body weight) in JCR rats decreased MMP12 activation, elastin degradation and large artery stiffness to levels achieved with 20‐SOLA and observed in SD control rats, suggesting: 1) that this 20‐HETE is largely derived from visceral (intra‐abdominal) adipose tissue, and 2) that MMP12 involved in the regulation of vascular stiffness is also derived primarily from visceral adipose tissue. Future implications of these findings may be important for systolic hypertension management through 20‐HETE and/or MMP12 inhibition.Support or Funding InformationSupported by NIH R01HL093052.