Autophagy regulates trans fatty acid-mediated apoptosis in primary cardiac myofibroblasts

作者：Ghavami Saeid; Cunnington Ryan H; Yeganeh Behzad; Davies Jared J L; Rattan Sunil G; Bathe Krista; Kavosh Morvarid; Los Marek J; Freed Darren H; Klonisch Thomas; Pierce Grant N; Halayko Andrew J; Dixon Ian M C^*

来源：Biochimica et Biophysica Acta-Molecular Cell Research, 2012, 1823(12): 2274-2286.

DOI：10.1016/j.bbamcr.2012.09.008

• Myofibroblast
• Trans fat
• Vaccenic acid
• Elaidic acid
• Autophagy
• Apoptosis

Trans fats are not a homogeneous group of molecules and less is known about the cellular effects of individual members of the group. Vaccenic acid (VA) and elaidic acid (EA) are the predominant trans monoenes in ruminant fats and vegetable oil, respectively. Here, we investigated the mechanism of cell death induced by VA and EA on primary rat ventricular myofibroblasts (rVF). The MIT assay demonstrated that both VA and EA (200 mu M, 0-72 h) reduced cell viability in rVF (P%26lt;0.001). The FACS assay confirmed that both VA and EA induced apoptosis in rVF, and this was concomitant with elevation in cleaved caspase-9, -3 and -7, but not caspase-8. VA and EA decreased the expression ratio of Bcl2:Bax, induced Bax translocation to mitochondria and decrease in mitochondrial membrane potential (Delta psi). BAX and BAX/BAK silencing in mouse embryonic fibroblasts (MEF) inhibited VA and EA-induced cell death compared to the corresponding wild type cells. Transmission electron microscopy revealed that VA and EA also induced macroautophagosome formation in rVF, and immunoblot analysis confirmed the induction of several autophagy markers: LC3-beta lipidation, Atg5-12 accumulation, and increased beclin-1. Finally, deletion of autophagy genes, ATG3 and ATG5 significantly inhibited VA and EA-induced cell death (P%26lt;0.001). Our findings show for the first time that trans fat acid (TFA) induces simultaneous apoptosis and autophagy in rVF. Furthermore, TFA-induced autophagy is required for this pro-apoptotic effect. Further studies to address the effect of TFA on the heart may reveal significant translational value for prevention of TFA-linked heart disease.

• 出版日期2012-12