Peroxisome Proliferator-Activated Receptor γ Coactivator-1α Is a Central Negative Regulator of Vascular Senescence

Xiong, Shiqin; Salazar, Gloria; Patrushev, Nikolay; Ma, Minhui; Forouzandeh, Farshad; Hilenski, Lula; Alexander, R. Wayne

doi:10.1161/atvbaha.112.301019

Cited by 75 publications

(77 citation statements)

References 47 publications

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“…SIRT1, as an important class III histone deacetylase, participates in many cell functions, i.e., senescence, proliferation, differentiation, and apoptosis [2,29,30]. It has been shown that mammalian SIRT1 is involved in chromatin remodeling, gene silencing, DNA damage response [31], and caloric restriction [32].…”

Section: Discussionmentioning

confidence: 99%

SIRT1 and FOXO Mediate Contractile Differentiation of Vascular Smooth Muscle Cells under Cyclic Stretch

Huang

Yan

Zhao

et al. 2015

Cell Physiol Biochem

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Background/Aims: Physiological mechanical stretch in vivo helps to maintain the quiescent contractile differentiation of vascular smooth muscle cells (VSMCs), but the underlying mechanisms are still unclear. Here, we investigated the effects of SIRT1 in VSMC differentiation in response to mechanical cyclic stretch. Methods and Results: Rat VSMCs were subjected to 10%-1.25Hz-cyclic stretch in vitro using a FX-4000T system. The data indicated that the expression of contractile markers, including α-actin, calponin and SM22α, was significantly enhanced in VSMCs that were subjected to cyclic stretch compared to the static controls. The expression of SIRT1 and FOXO3a was increased by the stretch, but the expression of FOXO4 was decreased. Decreasing SIRT1 by siRNA transfection attenuated the stretch-induced expression of contractile VSMC markers and FOXO3a. Furthermore, increasing SIRT1 by either treatment with activator resveratrol or transfection with a plasmid to induce overexpression increased the expression of FOXO3a and contractile markers, and decreased the expression of FOXO4 in VSMCs. Similar trends were observed in VSMCs of SIRT1 (+/-) knockout mice. The overexpression of FOXO3a promoted the expression of contractile markers in VSMCs, while the overexpression of FOXO4 demonstrated the opposite effect. Conclusion: Our results indicated that physiological cyclic stretch promotes the contractile differentiation of VSMCs via the SIRT1/FOXO pathways and thus contributes to maintaining vascular homeostasis.

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Section: Discussionmentioning

confidence: 99%

SIRT1 and FOXO Mediate Contractile Differentiation of Vascular Smooth Muscle Cells under Cyclic Stretch

Huang

Yan

Zhao

et al. 2015

Cell Physiol Biochem

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“…Apoptosis, defined as programmed cell death, also serves a homeostasis function through the regulation of cell death upon stress [7.] Senescence also contributes to the development of diabetic complications and age-related diseases [8]. There are complex relationships within autophagy, apoptosis and senescence.…”

Section: Introductionmentioning

confidence: 99%

“…Disrupting RAS has been shown to provide significant benefit for cellular function, and this effect has been shown to be reliant on mitochondrial-ROS [12,13,14,15]. Angiotensin II (Ang) exposure or overexpression of Ang type 1 receptor (AGTR1)-coupled-G-protein, Gaq, induces excessive ROS production and triggers autophagy, senescence and apoptosis in cardiomyocytes and smooth muscle cells [8,16,17]. However, whether RAS activity is increased and whether there is benefit to the use of angiotensin-converting enzyme inhibitors (ACEIs) or angiotensin II type 1 receptor blockers (ARBs) in diabetic patients without cardiovascular complications remains controversial.…”

Section: Introductionmentioning

confidence: 99%

Autophagy Protects Against Senescence and Apoptosis via the RAS-Mitochondria in High-Glucose-Induced Endothelial Cells

Chen

Bin

Xiao

et al. 2014

Cell Physiol Biochem

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Backgrounds: Autophagy is an important process in the pathogenesis of diabetes and plays a critical role in maintaining cellular homeostasis. However, the autophagic response and its mechanism in diabetic vascular endothelium remain unclear. Methods and Results: We studied high-glucose-induced renin-angiotensin system (RAS)-mitochondrial damage and its effect on endothelial cells. With regard to therapeutics, we investigated the beneficial effect of angiotensin-converting enzyme inhibitors (ACEIs) or angiotensin II type 1 receptor blockers (ARBs) against high-glucose-induced endothelial responses. High glucose activated RAS, enhanced mitochondrial damage and increased senescence, apoptosis and autophagic-responses in endothelial cells, and these effects were mimicked by using angiotensin II (Ang). The use of an ACEI or ARB, however, inhibited the negative effects of high glucose. Direct mitochondrial injury caused by carbonyl cyanide 3-chlorophenylhydrazone (CCCP) resulted in similar negative effects of high glucose or Ang and abrogated the protective effects of an ACEI or ARB. Additionally, by impairing autophagy, high-glucose-induced senescence and apoptosis were accelerated and the ACEI- or ARB-mediated beneficial effects were abolished. Furthermore, increases in FragEL™ DNA Fragmentation (TUNEL)-positive cells, β-galactosidase activation and the expression of autophagic biomarkers were revealed in diabetic patients and rats, and the treatment with an ACEI or ARB decreased these responses. Conclusions: These data suggest that autophagy protects against senescence and apoptosis via RAS-mitochondria in high-glucose-induced endothelial cells.

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“…In mice lacking telomerase, up to 4 generations may be required for such effects to be observed [3]. However, even in mice, shortened telomeres arise and characterize certain pathologies, such as atherosclerosis [4]. Telomeres of humans are significantly shorter than in mice: on the one hand it is thought that short telomeres may contribute to aging-related immune dysfunction, but on the other hand protect humans from cancer [5].…”

Section: Introductionmentioning

confidence: 99%

“…This effect results in more severe atherosclerosis, as well as vascular senescence characterized by reduced TERT, SIRT1 and catalase, as well as increased p53 expression. Thus PGC-1a may play a key role in preventing vascular senescence and atherosclerosis [4].…”

Section: Introductionmentioning

confidence: 99%

Telomerase Reverse Transcriptase and Peroxisome Proliferator-Activated Receptor γ Co-Activator-1α Cooperate to Protect Cells from DNA Damage and Mitochondrial Dysfunction in Vascular Senescence

Mendelsohn

Larrick

2015

Rejuvenation Research

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Reduced telomere length with increasing age in dividing cells has been implicated in contributing to the pathologies of human aging, which include cardiovascular and metabolic disorders, through induction of cellular senescence. Telomere shortening results from the absence of telomerase, an enzyme required to maintain telomere length. Telomerase reverse transcriptase (TERT), the protein subunit of telomerase, is expressed only transiently in a subset of adult somatic cells, which include stem cells and smooth muscle cells. A recent report from Xiong and colleagues demonstrates a pivotal role for the transcription co-factor peroxisome proliferator-activated receptor γ co-activator-1α (PGC-1α) in maintaining TERT expression and preventing vascular senescence and atherosclerosis in mice. Ablation of PGC-1α reduced TERT expression and increased DNA damage and reactive oxygen species (ROS), resulting in shortened telomeres and vascular senescence. In the ApoE(-/-) mouse model of atherosclerosis, forced expression of PGC-1α increased expression of TERT, extended telomeres, and reversed genomic DNA damage, vascular senescence, and the development of atherosclerotic plaques. Alpha lipoic acid (ALA) stimulated expression of PGC-1α and TERT and reversed DNA damage, vascular senescence, and atherosclerosis, similarly to ectopic expression of PGC-1α. ALA stimulated cyclic adenosine monophosphate (cAMP) signaling, which in turn activated the cAMP response element-binding protein (CREB), a co-factor for PGC-1α expression. The possibility that ALA might induce TERT to extend telomeres in human cells suggests that ALA may be useful in treating atherosclerosis and other aging-related diseases. However, further investigation is needed to identify whether ALA induces TERT in human cells, which cell types are susceptible, and whether such changes have clinical significance.

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Peroxisome Proliferator-Activated Receptor γ Coactivator-1α Is a Central Negative Regulator of Vascular Senescence

Cited by 75 publications

References 47 publications

SIRT1 and FOXO Mediate Contractile Differentiation of Vascular Smooth Muscle Cells under Cyclic Stretch

SIRT1 and FOXO Mediate Contractile Differentiation of Vascular Smooth Muscle Cells under Cyclic Stretch

Autophagy Protects Against Senescence and Apoptosis via the RAS-Mitochondria in High-Glucose-Induced Endothelial Cells

Telomerase Reverse Transcriptase and Peroxisome Proliferator-Activated Receptor γ Co-Activator-1α Cooperate to Protect Cells from DNA Damage and Mitochondrial Dysfunction in Vascular Senescence

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