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GIANNOTTI, K. C. Study on the effects of two phospholipases A2 (MT-III and BthTx-II) isolated from Bothrops snake venoms in vascular smooth muscle cells: lipid droplets formation and mechanisms involved. 2017. 141 p. Ph. D. thesis (Immunology) – Instituto de Ciências Biomédicas, Universidade de São Paulo, São Paulo, 2017. Bothrops snake venom GIIA secreted phospholipases A2 (sPLA2s) share structural and functional features with mammalian GIIA sPLA2s, which are highly expressed during inflammatory diseases, such as atherosclerosis. In this disease, vascular smooth muscle cells (VSMCs) are loaded with lipids in form of lipid droples (LDs) and differentiate into foam cells. However, the role of these enzymes in this process is still unknown. The aim of this study was to evaluate the effects of the snake venom PLA2 MT-III, with catalytic activity and BthTx-II, devoid of enzymatic activity, in VSMCs, with focus on LDs formation and mechanisms involved in this effect. Results here obtained demonstrate that both MT-III and BthTx-II were able to induce LDs formation in VSMCs in synthetic, but not contractile phenotype. Moreover, BthTx-II, but not MT-III, increased PLIN2 protein expression. In contrast, these FLA2s did not modify PLIN3 protein content. Both perilipins were recruited to LDs in cells stimulated either with MT-III or BthTx-II. In addition, BthTxII, but not MT-III, induced CD36 protein expression. Both PLA2s up-regulated SR-A1 and LOX-1 protein expression. However, these receptors were not involved in LDs formation induced by these venom PLA2s. Both MT-III and BthTx-II up-regulated and activated PPAR-γ e PPAR β/δ transcription factors. Moreover, blockage of these receptors as well as the enzymes DGAT (acyl CoA:diacylglycerol acyltransferase) and ACAT (acylcoenzyme A (CoA):cholesterol acyltransferase) abolished LD formation in VSMCs incubated with either MT-III or BthTx-II. Both PLA2s increased COX-2, but not COX-1 protein expression. Both COX-1 and COX-2 colocalized to LDs. However, the products from these two pathways are not involved in LDs formation. Same result was obtained when cells were incubated with an inhibitor of cPLA2. However, pre-treatment of cells with iPLA2 inhibitor reduced LDs formation induced by BthTx-II, but not MT-III. Inhibition of PI3K, a signaling protein relevant for macropinocytosis, also reduced LDs formation in VSMCs incubated with both PLA2s. These PLA2s induced release of IL-6, MCP-1, fractalkine, PGE2, PGI2 and TXA2. PGE2 was shown colocalized to LDs upon stimulation by both PLA2s. Finally, MT-III induced phagocytic activity and gene expression of CD68 and MAC-2 molecules, both recognized as macrophages markers. In conclusion, data here obtained indicate that MT-III and BthTx-II are able to induce formation of foam VSMCs and recruitment of distinct factors involved in synthesis and storage of lipids in these cells. In this condition, LDs constitute sites for synthesis of prostaglandins. Moreover, our findings show the ability of MT-III to modulate VSMCs functions, leading them to a phenotipic switch to macrophage-like cells. The catalytic activity is not relevant to ophidic sPLA2-induced LDs formation.

Estudo dos efeitos de duas fosfolipases A&lt;sub&gt;2&lt;/sub&gt; (MT-III e BthTx-II) isoladas do venenos de serpentes &lt;i&gt;Bothrops&lt;/i&gt; em células de músculo liso vascular em cultura: formação de corpúsculos lipídicos e mecanismos envolvidos.