PDF(Pubmed)
Abstract：
Arterial stiffness plays a causal role in development of systolic hypertension. 20-hydroxyeicosatetraeonic acid (20-HETE), a cytochrome P450 (CYP450)-derived arachidonic acid metabolite, is known to be elevated in resistance arteries in hypertensive animal models and loosely associated with obesity in humans. However, the role of 20-HETE in the regulation of large artery remodeling in metabolic syndrome has not been investigated. We hypothesized that elevated 20-HETE in metabolic syndrome increases matrix metalloproteinase 12 (MMP12) activation leading to increased degradation of elastin, increased large artery stiffness and increased systolic blood pressure. 20-HETE production was increased ~7 fold in large, conduit arteries of metabolic syndrome (JCR:LA-cp, JCR) vs. normal Sprague-Dawley (SD) rats. This correlated with increased elastin degradation (~7 fold) and decreased arterial compliance (~75% JCR vs. SD). 20-HETE antagonists blocked elastin degradation in JCR rats concomitant with blocking MMP12 activation. 20-HETE antagonists normalized, and MMP12 inhibition (pharmacological and MMP12-shRNA-Lnv) significantly improved (~50% vs. untreated JCR) large artery compliance in JCR rats. 20-HETE antagonists also decreased systolic (182 ± 3 mmHg JCR, 145 ± 3 mmHg JCR + 20-HETE antagonists) but not diastolic 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 was Ang II-independent. Thus, 20-HETE-dependent regulation of systolic blood pressure may be a unique feature of metabolic syndrome related to high 20-HETE production in large, conduit arteries, which results in increased large artery stiffness and systolic blood pressure. These findings may have implications for management of systolic hypertension in patients with metabolic syndrome.
摘要：
动脉僵硬在收缩期高血压的发展中起着因果关系。20-羟基二十烷酸酯四烯酸(20-HETE)，细胞色素P450（CYP450）衍生的花生四烯酸代谢物，已知在高血压动物模型的阻力动脉中升高，并且与人类肥胖松散相关。然而,尚未研究20-HETE在调节代谢综合征大动脉重塑中的作用.我们假设代谢综合征中20-HETE升高会增加基质金属蛋白酶12（MMP12）的活化，导致弹性蛋白降解增加，大动脉僵硬度增加，收缩压升高。20-HETE产量增加了约7倍，代谢综合征的导管动脉（JCR：LA-cp，JCR）与正常SD大鼠。这与增加的弹性蛋白降解（约7倍）和降低的动脉顺应性（约75％JCRvs.SD）。20-HETE拮抗剂阻断JCR大鼠中的弹性蛋白降解,同时阻断MMP12活化。20-HETE拮抗剂正常化，和MMP12抑制（药理学和MMP12-shRNA-Lnv）显着改善（〜50％vs.未经治疗的JCR）JCR大鼠的大动脉顺应性。20-HETE拮抗剂也降低了收缩压（182±3mmHgJCR，145±3mmHgJCR20-HETE拮抗剂），而不是JCR大鼠的舒张压。而舒张压完全依赖于血管紧张素II（AngII），收缩压仅部分依赖AngII，大动脉僵硬度是AngⅡ非依赖性。因此，20-HETE依赖性收缩压调节可能是代谢综合征的一个独特特征，与高20-HETE产量相关，导管动脉,导致大动脉僵硬度和收缩压增加。这些发现可能对代谢综合征患者收缩期高血压的管理有启示。
