IPLA ₂β overexpression in smooth muscle exacerbates angiotensin II-induced hypertension and vascular remodeling

Objectives: Calcium independent group VIA phospholipase A ₂ (iPLA ₂β) is up-regulated in vascular smooth muscle cells in some diseases, but whether the up-regulated iPLA ₂β 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 ₂β transgenic (iPLA ₂β -Tg) mice. Method and Results: 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 ₂β-Tg than iPLA ₂β-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 ₂β-Tg mice. Analysis revealed no difference in vascular smooth muscle cell proliferation. In contrast, adenovirus-mediated iPLA ₂β overexpression in cultured vascular smooth muscle cells promoted angiotensin II-induced [ ³H]-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 ₂β protein in-vitro and in-vivo. Conclusion: The present study reports that iPLA ₂β up-regulation exacerbates angiotensin II-induced vascular smooth muscle cell hypertrophy, vascular remodeling and hypertension via the 12/15 lipoxygenase and c-Jun pathways.