Smooth muscle-specific expression of calcium-independent phospholipase A₂β (iPLA₂β) participates in the initiation and early progression of vascular inflammation and neointima formation

Whether group VIA phospholipase A₂ (iPLA₂β) is involved in vascular inflammation and neointima formation is largely unknown. Here, we report that iPLA₂β expression increases in the vascular tunica media upon carotid artery ligation and that neointima formation is suppressed by genetic deletion of iPLA₂β or by inhibiting its activity or expression via perivascular delivery of bromoenol lactone or of antisense oligonucleotides, respectively. To investigate whether smooth muscle-specific iPLA₂β is involved in neointima formation, we generated transgenic mice in which iPLA₂β is expressed specifically in smooth muscle cells and demonstrate that smooth muscle-specific expression of iPLA₂β exacerbates ligation-induced neointima formation and enhanced both production of proinflammatory cytokines and vascular infiltration by macrophages. With cultured vascular smooth muscle cell, angiotensin II, arachidonic acid, and TNF-α markedly induce increased expression of IL-6 and TNF-α mRNAs, all of which were suppressed by inhibiting iPLA₂β activity or expression with bromoenol lactone, antisense oligonucleotides, and genetic deletion, respectively. Similar suppression also results from genetic deletion of 12/15-lipoxygenase or inhibiting its activity with nordihydroguaiaretic acid or luteolin. Expression of iPLA₂βprotein in cultured vascular smooth muscle cells was found to depend on the phenotypic state and to rise upon incubation with TNF-&alpha. Our studies thus illustrate that smooth muscle cell-specific iPLA₂α participates in the initiation and early progression of vascular inflammation and neointima formation and suggest that iPLA ₂α may represent a novel therapeutic target for preventing cardiovascular diseases.