Large artery stiffness plays a causal role in development of systolic hypertension. Isolated systolic hypertension is particularly difficult to manage due to currently available anti- hypertensive drugs' equal effect on both systolic and diastolic blood pressure, and consequential lowering of diastolic blood pressure to excessively low levels resulting in symptomatic organ hypoperfusion, or inadequate lowering of systolic blood pressure. 20- hydroxyeicosatetraeonic acid (20-HETE), a cytochrome (CYP)-derived arachidonic acid metabolite, is elevated in hypertensive animal models and associated with obesity in humans. Our preliminary data show that 20-HETE is an angiotensin II-independent regulator of systolic, but not diastolic blood pressure in hypertensive metabolic syndrome rats (JCR). Large artery stiffness, a major determinant of systolic blood pressure, was also elevated in JCR rats and decreased to that observed in normal (Sprague-Dawley, SD) rats by 20-HETE antagonists. Elastin degradation, a major determinant of large artery stiffness, was increased in JCR rats and reversed by 20-HETE antagonists. Elastin is the main substrate for matrix metalloproteinase 12 (MMP12). MMP12 activation was significantly increased in JCR vs. SD rats and inhibited by 20- HETE antagonists. The source(s) of 20-HETE and MMP12 responsible for increased elastin degradation and large artery stiffness are unknown. Intra-abdominal lipectomy in JCR rats decreased MMP12 activation, elastin degradation and large artery stiffness to levels seen in SD rats, suggesting that this 20-HETE and MMP12 are largely derived from visceral adipose tissue. Thus, we hypothesize that elevated 20-HETE in metabolic syndrome increases MMP12 activation leading to increased elastin degradation, large artery stiffness and increased systolic blood pressure. This hypothesis will be addressed in three aims: 1) Whether 20-HETE is a major determinant of MMP12 activation, elastin degradation, large artery stiffness and increased systolic blood pressure in metabolic syndrome; 2) Whether 20-HETE-dependent MMP12 activation is a major determinant of large artery stiffness and systolic blood pressure in metabolic syndrome; and 3) Whether arterial wall or visceral adipose tissue is the major source of 20-HETE and MMP12 responsible for increased large artery stiffness and systolic blood pressure in metabolic syndrome. Findings from these studies may be important for management of isolated systolic hypertension.
The percentage of people in whom blood pressure is not well controlled is increasing. Isolated systolic hypertension is associated with increased incidence of end organ damage and stroke. Co-existence of hypertension and obesity, as in metabolic syndrome, is associated with 6-fold increase in stroke and 4-fold increase in myocardial infarction vs. either condition alone. Current antihypertensive therapy does not specifically target systolic blood pressure and is associated with increased side-effects in patients with isolated systolic hypertension. The proposed studies will identify novel pharmacological therapy to specifically target systolic blood pressure in metabolic syndrome, with no projected adverse effect on humans.
| Soler, Amanda; Hunter, Ian; Joseph, Gregory et al. (2018) Elevated 20-HETE in metabolic syndrome regulates arterial stiffness and systolic hypertension via MMP12 activation. J Mol Cell Cardiol 117:88-99 |
