Tyrrell 2019 Circ Res

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Tyrrell DJ, Blin M, Song J, Wood S, Zhang M, Beard DA, Goldstein D (2019) Age-associated mitochondrial dysfunction accelerates atherogenesis. Circ Res 126:298–314.

» PMID: 31818196 Open Access

Tyrrell DJ, Blin M, Song J, Wood S, Zhang M, Beard DA, Goldstein D (2019) Circ Res

Abstract: Aging is one of the strongest risk factors for atherosclerosis. Yet whether aging increases the risk of atherosclerosis independently of chronic hyperlipidemia is not known.

The objective was to determine if vascular aging prior to the induction of hyperlipidemia enhances atherogenesis.

We analyzed the aortas of young and aged normolipidemic wild type (WT), disease free mice and found that aging led to elevated IL-6 levels and mitochondrial dysfunction, associated with increased mitophagy and the associated protein Parkin. In aortic tissue culture, we found evidence that with aging mitochondrial dysfunction and IL-6 exist in a positive feedback loop. We triggered acute hyperlipidemia in aged and young mice by inducing liver-specific degradation of the LDL receptor combined with a 10-week western diet and found that atherogenesis was enhanced in aged WT mice. Hyperlipidemia further reduced mitochondrial function and increased the levels of Parkin in the aortas of aged mice but not young mice. Genetic disruption of autophagy in smooth muscle cells of young mice exposed to hyperlipidemia led to increased aortic Parkin and IL-6 levels, impaired mitochondrial function, and enhanced atherogenesis. Importantly, enhancing mitophagy in aged, hyperlipidemic mice via oral administration of spermidine prevented the increase in aortic IL-6 and Parkin, attenuated mitochondrial dysfunction, and reduced atherogenesis.

Prior to hyperlipidemia, aging elevates IL-6 and impairs mitochondrial function within the aorta, associated with enhanced mitophagy and increased Parkin levels. These age-associated changes prime the vasculature to exacerbate atherogenesis upon acute hyperlipidemia. Our work implies that novel therapeutics aimed at improving vascular mitochondrial bioenergetics or reducing inflammation before hyperlipidemia may reduce age-related atherosclerosis.

Keywords: Atherosclerosis, Aging, Hyperlipidemia, Mitochondria, Animal model of cardiovascular disease, Vascular biology, Atherogenesis Bioblast editor: Plangger M O2k-Network Lab: US MI Ann Arbor Beard DA


Labels: MiParea: Respiration, Exercise physiology;nutrition;life style, Pharmacology;toxicology  Pathology: Aging;senescence 

Organism: Mouse  Tissue;cell: Endothelial;epithelial;mesothelial cell 


Coupling state: OXPHOS, ET  Pathway: N, S, NS, ROX  HRR: Oxygraph-2k 

Labels, 2020-01, Spermidine, Alert2020, mitObesity2020