The age-dependent development of abnormal cardiac metabolism in the peroxisome proliferator-activated receptor α-knockout mouse.

IF 4.9 2区 医学 Q1 CARDIAC & CARDIOVASCULAR SYSTEMS Atherosclerosis Pub Date : 2024-09-17 DOI:10.1016/j.atherosclerosis.2024.118599
Michael S Dodd, Lucy Ambrose, Vicky Ball, Kieran Clarke, Carolyn A Carr, Damian J Tyler
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Abstract

Background and aims: Peroxisome proliferator-activated receptor α (PPARα) is crucial for regulating cardiac β-oxidation in the heart, liver, and kidney. Ageing can induce cardiac metabolic alterations, but the role of PPARα has not been extensively characterised. The aim of this research was to investigate the role of PPARα in the aged heart.

Methods: Hyperpolarized [1-13C]pyruvate was used to evaluate in vivo cardiac carbohydrate metabolism in fed and fasted young (3 months) and old (20-22 months) PPARα knockout (KO) mice versus controls. Cine MRI assessed cardiac structural and functional changes. Cardiac tissue analysis included qRT-PCR and Western blotting for Pparα, medium chain acyl-CoA dehydrenase (MCAD), uncoupling protein (UCP) 3, glucose transporter (GLUT) 4 and PDH kinase (PDK) 1,2, and 4 expression.

Results: PPARα-KO hearts from both young and old mice showed significantly reduced Pparα mRNA and a 58-59 % decrease in MCAD protein levels compared to controls. Cardiac PDH flux was similar in young control and PPARα-KO mice but 96 % higher in old PPARα-KO mice. Differences between genotypes were consistent in fed and fasted states, with reduced PDH flux when fasted. Increased PDH flux was accompanied by a 179 % rise in myocardial GLUT4 protein. No differences in PDK 1, 2, or 4 protein levels were observed between fed groups, indicating the increased PDH flux in aged PPARα-KO mice was not due to changes in PDH phosphorylation.

Conclusions: Aged PPARα-KO mice demonstrated higher cardiac PDH flux compared to controls, facilitated by increased myocardial GLUT4 protein levels, leading to enhanced glucose uptake and glycolysis.

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过氧化物酶体增殖激活受体α基因敲除小鼠心脏代谢异常的发展与年龄有关。
背景和目的:过氧化物酶体增殖激活受体α(PPARα)是调节心脏、肝脏和肾脏中心脏β氧化作用的关键。衰老可诱发心脏代谢改变,但 PPARα 的作用尚未得到广泛表征。研究方法:使用超极化[1-13C]丙酮酸评估幼年(3 个月)和老年(20-22 个月)PPARα 基因敲除(KO)小鼠与对照组的体内心脏碳水化合物代谢。显像核磁共振成像评估了心脏结构和功能的变化。心脏组织分析包括 Pparα、中链酰基-CoA 脱氢酶(MCAD)、解偶联蛋白(UCP)3、葡萄糖转运体(GLUT)4 和 PDH 激酶(PDK)1、2 和 4 表达的 qRT-PCR 和 Western 印迹检测:结果:与对照组相比,年轻和年老小鼠的 PPARα-KO 心脏的 Pparα mRNA 显著减少,MCAD 蛋白水平下降了 58-59%。年轻对照组和 PPARα-KO 小鼠的心脏 PDH 通量相似,但老年 PPARα-KO 小鼠的 PDH 通量比对照组高 96%。基因型之间的差异在进食和禁食状态下是一致的,禁食时 PDH 通量降低。PDH 通量增加的同时,心肌 GLUT4 蛋白也增加了 179%。喂养组之间的 PDK 1、2 或 4 蛋白水平没有差异,这表明老龄 PPARα-KO 小鼠 PDH 通量的增加不是由于 PDH 磷酸化的变化:结论:与对照组相比,老年 PPARα-KO 小鼠表现出更高的心脏 PDH 通量,心肌 GLUT4 蛋白水平的增加促进了 PDH 通量的增加,从而导致葡萄糖摄取和糖酵解的增强。
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来源期刊
Atherosclerosis
Atherosclerosis 医学-外周血管病
CiteScore
9.80
自引率
3.80%
发文量
1269
审稿时长
36 days
期刊介绍: Atherosclerosis has an open access mirror journal Atherosclerosis: X, sharing the same aims and scope, editorial team, submission system and rigorous peer review. Atherosclerosis brings together, from all sources, papers concerned with investigation on atherosclerosis, its risk factors and clinical manifestations. Atherosclerosis covers basic and translational, clinical and population research approaches to arterial and vascular biology and disease, as well as their risk factors including: disturbances of lipid and lipoprotein metabolism, diabetes and hypertension, thrombosis, and inflammation. The Editors are interested in original or review papers dealing with the pathogenesis, environmental, genetic and epigenetic basis, diagnosis or treatment of atherosclerosis and related diseases as well as their risk factors.
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