A Secreted Phospholipase A(2) Induces Formation of Smooth Muscle Foam Cells Which Transdifferentiate to Macrophage-Like State

Author(s)

Giannotti, Karina Cristina ^[1] ; Weinert, Soenke ^[2] ; Viana, Mariana Nascimento ^[1] ; Leiguez, Elbio ^[1] ; Araujo, Thais L. S. ^[3] ; Laurindo, Francisco R. M. ^[3] ; Lomonte, Bruno ^[4] ; Braun-Dullaeus, Ruediger ^[2] ; Teixeira, Catarina ^[1]

Affiliation

^[1] Butantan Inst, Pharmacol Lab, BR-05503900 Sao Paulo - Brazil

^[2] Otto von Guericke Univ, Dept Cardiol & Angiol, Internal Med, D-39120 Magdeburg - Germany

^[3] Univ Sao Paulo, Sch Med, Vasc Biol Lab Heart Inst InCor, BR-01246903 Sao Paulo - Brazil

^[4] Univ Costa Rica, Inst Clodomiro Picado Inst, San Jose 11501 - Costa Rica

• Document type: Journal article
• Source: Molecules; v. 24, n. 18 SEP 2019.
• Web of Science Citations: 0

Abstract

Vascular smooth muscle cells (VSMCs) loaded with lipid droplets (LDs) are markers of atherosclerosis. In this disease, inflammatory Group IIA-secreted phospholipase A(2)s (GIIA sPLA(2)s) are highly expressed in VSMCs, but their actions in these cells are unknown. Here, we investigated the ability of myotoxin III (MT-III), an ophidian GIIA sPLA(2) sharing structural and functional features with mammalian GIIA sPLA(2)s, to induce LD formation and lipid metabolism factors involved in this effect. Modulation of VSMC phenotypes by this sPLA(2) was also evaluated. Incubation of VSMCs with MT-III significantly increased the number of LDs. MT-III upregulated scavenger receptor type 1 (SR-A1) and lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1) protein expression and enhanced acetylated-low density lipoprotein (acLDL) uptake by VSMCs, revealing the ability of a GIIA PLA(2) to modulate scavenger receptor activities. MT-III induced translocation and protein expression of PPAR-gamma and -beta/delta. Inhibition of peroxisome proliferator-activated receptors (PPARs) and diacylglycerol O-acyltransferase (DGAT) and acyl-CoA:cholesterolacyltransferase (ACAT) enzymes abrogated MT-III-induced LD formation. Moreover, in response to MT-III, VSMCs acquired phagocytic activity and expressed macrophage markers CD68 and MAC-2. In conclusion, MT-III is able to stimulate VSMCs and recruit factors involved in lipid uptake and metabolism, leading to the formation of VSMC-derived foam cells with acquisition of macrophage-like markers and functions. (AU)

• FAPESP's process: 13/22610-5 - Studies on the effects of a phospholipase A2 isolated from Bothrops asper snake venom on smooth muscle vascular cells in culture. Formation of Lipid Droplets and mechanisms involved in this effect.
• Grantee: Karina Cristina Giannotti
• Support Opportunities: Scholarships in Brazil - Doctorate
• FAPESP's process: 15/24701-3 - Studies of effects of a snake venom phospholipase A2 on cells from the adipose tissue: Adipogenesis and inflammatory response
• Grantee: Elbio Leiguez Junior
• Support Opportunities: Scholarships in Brazil - Post-Doctoral
• FAPESP's process: 16/14046-0 - Study on the effects of MT-III, a snake venom secreted phospholipase A2 (sPLA2), on isolated rat and human aortic vascular smooth muscle cells: Dedifferentiation into a phagocytic active macrophage-like phenotype
• Grantee: Karina Cristina Giannotti
• Support Opportunities: Scholarships abroad - Research Internship - Doctorate
• FAPESP's process: 14/18549-1 - Characterization of the effects of a snake venom Phospholipase A2 (MT-III) on smooth muscle vascular cells in culture: formation of foam cells and mechanisms involved in this effect
• Grantee: Catarina de Fatima Pereira Teixeira
• Support Opportunities: Regular Research Grants