دورية
Abstract 13103: Defective Vascular Smooth Muscle Cell Tafazzin Impairs Mitochondrial Function and Promotes Atherosclerosis
| العنوان: | Abstract 13103: Defective Vascular Smooth Muscle Cell Tafazzin Impairs Mitochondrial Function and Promotes Atherosclerosis |
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| المؤلفون: | Dong, Cindy, Finigan, Alison, Figg, Nichola, Bennett, Martin, Yu, Emma |
| المصدر: | Circulation (Ovid); November 2022, Vol. 146 Issue: Supplement 1 pA13103-A13103, 1p |
| مستخلص: | Introduction:Tafazzin acylates immature monolysocardiolipin to form mature cardiolipin. Cardiolipin is the signature phospholipid of the mitochondrial inner membrane required for respiratory efficiency and regulation of apoptosis. Mitochondrial respiration is reduced in atherosclerosis. However, whether tafazzin regulates vascular smooth mucle cell (VSMC) mitochondrial function and contributes to atherosclerosis is unclear.Hypothesis:Tafazzin regulates VSMC mitochondrial function and atherosclerosis development.Methods:We examined tafazzin expression and regulation in human plaques and VSMCs. We determined the in vitro effects of tafazzin using siRNA mediated cell silencing or lentiviral infection to express either tafazzin (Taz) or tafazzin with a transacylase defective mutation (TazH69Q). We also generated mice expressing VSMC restricted Taz or TazH69Qand crossed them with apolipoprotein E deficient mice (SM22α-Taz/ApoE-/-or SM22α-TazH69Q/ApoE-/-) to study tafazzin in vivoResults:Tafazzin mRNA and protein is decreased in plaque and plaque VSMCs. MicroRNA 125a-5p expression is increased in plaques, downregulates tafazzin expression and is induced by oxidised low density lipoprotein. Tafazzin silencing and expression of TazH69Qreduces mitochondrial respiration, decreases ATP content (0.13±0.01nmoles vs 0.21±0.01nmole, n=4), and promotes apoptosis. SM22α-TazH69Q/ApoE-/-mice showed increased plaque burden (28±2.3% vs 17±2.1%, n=17), increased necrotic core and reduced fibrous cap areas. In contrast, over-expression of tafazzin increases VSMC mitochondrial respiration and protects against apoptosis. SM22α-Taz/ApoE-/-mice showed no change in plaque burden but increased features of plaque stability. SS-31, which binds and stabilises cardiolipin, improves mitochondrial respiration and decreases apoptosis in SM22α-TazH69Q/ApoE-/-VSMCs.Conclusions:Tafazzin expression is decreased in plaque VSMCs and is negatively regulated by microRNA 125a-5p. Defective tafazzin decreases mitochondrial respiration, increases apoptosis and promotes atherosclerosis. Tafazzin is therefore an important and unrecognised regulator of VSMC mitochondrial function and atherosclerosis. |
| قاعدة البيانات: | Supplemental Index |
Full Text Finder | تدمد: | 00097322 15244539 |
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| DOI: | 10.1161/circ.146.suppl_1.13103 |