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Role of PGC-1? in Vascular Regulation: Implications for Atherosclerosis.

ABSTRACT: Mitochondrial dysfunction results in high levels of oxidative stress and mitochondrial damage, leading to disruption of endothelial homeostasis. Recent discoveries have clarified several pathways, whereby mitochondrial dysregulation contributes to endothelial dysfunction and vascular disease burden. One such pathway centers around peroxisome proliferator receptor-? coactivator 1? (PGC-1?), a transcriptional coactivator linked to mitochondrial biogenesis and antioxidant defense, among other functions. Although primarily investigated for its therapeutic potential in obesity and skeletal muscle differentiation, the ability of PGC-1? to alter a multitude of cellular functions has sparked interest in its role in the vasculature. Within this context, recent studies demonstrate that PGC-1? plays a key role in endothelial cell and smooth muscle cell regulation through effects on oxidative stress, apoptosis, inflammation, and cell proliferation. The ability of PGC-1? to affect these parameters is relevant to vascular disease progression, particularly in relation to atherosclerosis. Upregulation of PGC-1? can prevent the development of, and even encourage regression of, atherosclerotic lesions. Therefore, PGC-1? is poised to serve as a promising target in vascular disease. This review details recent findings related to PGC-1? in vascular regulation, regulation of PGC-1? itself, the role of PGC-1? in atherosclerosis, and therapies that target this key protein.

SUBMITTER: Kadlec AO

PROVIDER: S-EPMC4965312 | biostudies-literature | 2016 Aug

REPOSITORIES: biostudies-literature

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Role of PGC-1α in Vascular Regulation: Implications for Atherosclerosis.

Kadlec Andrew O AO Chabowski Dawid S DS Ait-Aissa Karima K Gutterman David D DD

Arteriosclerosis, thrombosis, and vascular biology 20160616 8

Mitochondrial dysfunction results in high levels of oxidative stress and mitochondrial damage, leading to disruption of endothelial homeostasis. Recent discoveries have clarified several pathways, whereby mitochondrial dysregulation contributes to endothelial dysfunction and vascular disease burden. One such pathway centers around peroxisome proliferator receptor-γ coactivator 1α (PGC-1α), a transcriptional coactivator linked to mitochondrial biogenesis and antioxidant defense, among other funct ...[more]

PMID: 27312223

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Project description:BackgroundAtherosclerosis is a chronic inflammatory disease that evolves from the interaction of activated endothelial cells, macrophages, lymphocytes and modified lipoproteins (LDLs). In the last years many molecules with crucial metabolic functions have been shown to prevent important steps in the progression of atherogenesis, including peroxisome proliferator activated receptors (PPARs) and the class III histone deacetylase (HDAC) SIRT1. The PPARγ coactivator 1 alpha (Ppargc1a or PGC-1α) was identified as an important transcriptional cofactor of PPARγ and is activated by SIRT1. The aim of this study was to analyze total PGC-1α deficiency in an atherosclerotic mouse model.Methodology/principal findingsTo investigate if total PGC-1α deficiency affects atherosclerosis, we compared ApoE(-/-) PGC-1α(-/-) and ApoE(-/-) PGC-1α(+/+) mice kept on a high cholesterol diet. Despite having more macrophages and a higher ICAM-1 expression in plaques, ApoE(-/-) PGC-1α(-/-) did not display more or larger atherosclerotic plaques than their ApoE(-/-) PGC-1α(+/+) littermates. In line with the previously published phenotype of PGC-1α(-/-) mice, ApoE(-/-) PGC-1α(-/-) mice had marked reduced body, liver and epididymal white adipose tissue (WAT) weight. VLDL/LDL-cholesterol and triglyceride contents were also reduced. Aortic expression of PPARα and PPARγ, two crucial regulators for adipocyte differentiation and glucose and lipid metabolism, as well as the expression of some PPAR target genes was significantly reduced in ApoE(-/-) PGC-1α(-/-) mice. Importantly, the epididymal WAT and aortic expression of IL-18 and IL-18 plasma levels, a pro-atherosclerotic cytokine, was markedly reduced in ApoE(-/-) PGC-1α(-/-) mice.Conclusions/significanceApoE(-/-) PGC-1α(-/-) mice, similar as PGC-1α(-/-) mice exhibit markedly reduced total body and visceral fat weight. Since inflammation of visceral fat is a crucial trigger of atherogenesis, decreased visceral fat in PGC-1α-deficient mice may explain why these mice do not develop enhanced atherosclerosis.

Dataset Information

Role of PGC-1? in Vascular Regulation: Implications for Atherosclerosis.

Publications

Role of PGC-1α in Vascular Regulation: Implications for Atherosclerosis.

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