Department of Molecular and Biomedical Pharmacology, University of Kentucky, Lexington, Kentucky, United States of America.
PLoS One. 2012;7(2):e31850. doi: 10.1371/journal.pone.0031850. Epub 2012 Feb 20.
Calcium independent group VIA phospholipase A(2) (iPLA(2)β) is up-regulated in vascular smooth muscle cells in some diseases, but whether the up-regulated iPLA(2)β affects vascular morphology and blood pressure is unknown. The current study addresses this question by evaluating the basal- and angiotensin II infusion-induced vascular remodeling and hypertension in smooth muscle specific iPLA(2)β transgenic (iPLA(2)β-Tg) mice.
Blood pressure was monitored by radiotelemetry and vascular remodeling was assessed by morphologic analysis. We found that the angiotensin II-induced increase in diastolic pressure was significantly higher in iPLA(2)β-Tg than iPLA(2)β-Wt mice, whereas, the basal blood pressure was not significantly different. The media thickness and media∶lumen ratio of the mesenteric arteries were significantly increased in angiotensin II-infused iPLA(2)β-Tg mice. Analysis revealed no difference in vascular smooth muscle cell proliferation. In contrast, adenovirus-mediated iPLA(2)β overexpression in cultured vascular smooth muscle cells promoted angiotensin II-induced [(3)H]-leucine incorporation, indicating enhanced hypertrophy. Moreover, angiotensin II infusion-induced c-Jun phosphorylation in vascular smooth muscle cells overexpressing iPLA2β to higher levels, which was abolished by inhibition of 12/15 lipoxygenase. In addition, we found that angiotensin II up-regulated the endogenous iPLA(2)β protein in-vitro and in-vivo.
The present study reports that iPLA(2)β up-regulation exacerbates angiotensin II-induced vascular smooth muscle cell hypertrophy, vascular remodeling and hypertension via the 12/15 lipoxygenase and c-Jun pathways.
钙非依赖性 VIA 组磷酯酶 A2（iPLA2β）在某些疾病的血管平滑肌细胞中被上调，但上调的 iPLA2β 是否会影响血管形态和血压尚不清楚。本研究通过评估平滑肌特异性 iPLA2β 转基因（iPLA2β-Tg）小鼠的基础和血管紧张素 II 输注诱导的血管重塑和高血压来解决这个问题。
通过无线电遥测监测血压，通过形态学分析评估血管重塑。我们发现，iPLA2β-Tg 小鼠的血管紧张素 II 诱导的舒张压增加明显高于 iPLA2β-Wt 小鼠，而基础血压无明显差异。肠系膜动脉中膜厚度和中膜：腔比在血管紧张素 II 输注的 iPLA2β-Tg 小鼠中显著增加。分析显示血管平滑肌细胞增殖无差异。相反，在培养的血管平滑肌细胞中，腺病毒介导的 iPLA2β 过表达促进了血管紧张素 II 诱导的[(3)H]-亮氨酸掺入，表明肥大增强。此外，血管紧张素 II 输注诱导的 c-Jun 在血管平滑肌细胞中磷酸化，iPLA2β 的表达水平更高，这一作用被 12/15 脂氧合酶的抑制所消除。此外，我们发现血管紧张素 II 在体外和体内均可上调内源性 iPLA2β 蛋白。
本研究报告称，iPLA2β 的上调通过 12/15 脂氧合酶和 c-Jun 途径加重了血管紧张素 II 诱导的血管平滑肌细胞肥大、血管重塑和高血压。
