The chemokine CCL17 is a novel therapeutic target for cardiovascular aging

Zhang, Yang; Tang, Xiaoqiang; Wang, Zeyuan; Wang, Lun; Chen, Zhangwei; Qian, Juying; Tian, Zhuang; Zhang, Shuyang

doi:10.1038/s41392-023-01363-1

Cited by 8 publications

(5 citation statements)

References 10 publications

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“…To further test the effects of SIRT2 on arterial constriction–relaxation function, the aortas were dissociated for an ex vivo functional study. 50 Phenylephrine-induced vascular constriction in endothelium-denuded aortas was impaired in aged mice and further deteriorated with SIRT2 deficiency ( Figure 2B ). Although endothelium-dependent relaxation was identical in aged WT and Sirt2 -KO mice ( Figure 2C ), aged Sirt2 -KO mice exhibited poorer endothelium-independent relaxation ( Figure 2D ).…”

Section: Resultsmentioning

confidence: 99%

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Sirtuin 2 deficiency aggravates ageing-induced vascular remodelling in humans and mice

Zhang

et al. 2023

European Heart Journal

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Aims The mechanisms underlying ageing-induced vascular remodelling remain unclear. This study investigates the role and underlying mechanisms of the cytoplasmic deacetylase sirtuin 2 (SIRT2) in ageing-induced vascular remodelling. Methods and results Transcriptome and quantitative real-time PCR data were used to analyse sirtuin expression. Young and old wild-type and Sirt2 knockout mice were used to explore vascular function and pathological remodelling. RNA-seq, histochemical staining, and biochemical assays were used to evaluate the effects of Sirt2 knockout on the vascular transcriptome and pathological remodelling and explore the underlying biochemical mechanisms. Among the sirtuins, SIRT2 had the highest levels in human and mouse aortas. Sirtuin 2 activity was reduced in aged aortas, and loss of SIRT2 accelerated vascular ageing. In old mice, SIRT2 deficiency aggravated ageing-induced arterial stiffness and constriction–relaxation dysfunction, accompanied by aortic remodelling (thickened vascular medial layers, breakage of elastin fibres, collagen deposition, and inflammation). Transcriptome and biochemical analyses revealed that the ageing-controlling protein p66Shc and metabolism of mitochondrial reactive oxygen species (mROS) contributed to SIRT2 function in vascular ageing. Sirtuin 2 repressed p66Shc activation and mROS production by deacetylating p66Shc at lysine 81. Elimination of reactive oxygen species by MnTBAP repressed the SIRT2 deficiency–mediated aggravation of vascular remodelling and dysfunction in angiotensin II–challenged and aged mice. The SIRT2 coexpression module in aortas was reduced with ageing across species and was a significant predictor of age-related aortic diseases in humans. Conclusion The deacetylase SIRT2 is a response to ageing that delays vascular ageing, and the cytoplasm–mitochondria axis (SIRT2–p66Shc–mROS) is important for vascular ageing. Therefore, SIRT2 may serve as a potential therapeutic target for vascular rejuvenation.

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Section: Resultsmentioning

confidence: 99%

“…One such example is our current finding that circulating CCL17 predicted cardiac and vascular ageing in humans and mice, and recombinant anti-CCL17 antibodies delayed cardiac and vascular ageing in animals. 49 , 50 …”

Section: Discussionmentioning

confidence: 99%

Sirtuin 2 deficiency aggravates ageing-induced vascular remodelling in humans and mice

Zhang

et al. 2023

European Heart Journal

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“…Mitochondrial dysfunction, inflammation, and myocardial fibrosis have long been considered as crucial underlying mechanisms responsible for the development of HF after MI. [6][7][8] The heart is a metabolically active organ, accounting for only 0.5% of the body weight but consuming nearly 8% of the total adenosine triphosphate(ATP). 9 In general, 95% of the ATP consumed by the heart is obtained from oxidative phosphorylation along the mitochondrial electron transport chain (ETC).…”

Section: Introductionmentioning

confidence: 99%

Reticulon 3 deficiency ameliorates post‐myocardial infarction heart failure by alleviating mitochondrial dysfunction and inflammation

Qi,

Li,

Luo

et al. 2024

MedComm

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Multiple molecular mechanisms are involved in the development of heart failure (HF) after myocardial infarction (MI). However, interventions targeting these pathological processes alone remain clinically ineffective. Therefore, it is essential to identify new therapeutic targets for alleviating cardiac dysfunction after MI. Here, gain‐ and loss‐of‐function approaches were used to investigate the role of reticulon 3 (RTN3) in HF after MI. We found that RTN3 was elevated in the myocardium of patients with HF and mice with MI. Cardiomyocyte‐specific RTN3 overexpression decreased systolic function in mice under physiological conditions and exacerbated the development of HF induced by MI. Conversely, RTN3 knockout alleviated cardiac dysfunction after MI. Mechanistically, RTN3 bound and mediated heat shock protein beta‐1 (HSPB1) translocation from the cytosol to the endoplasmic reticulum. The reduction of cytosolic HSPB1 was responsible for the elevation of TLR4, which impaired mitochondrial function and promoted inflammation through toll‐like receptor 4 (TLR4)/peroxisome proliferator‐activated receptor gamma coactivator‐1 alpha(PGC‐1α) and TLR4/Nuclear factor‐kappa B(NFκB) pathways, respectively. Furthermore, the HSPB1 inhibitor reversed the protective effect of RTN3 knockout on MI. Additionally, elevated plasma RTN3 level is associated with decreased cardiac function in patients with acute MI. This study identified RTN3 as a critical driver of HF after MI and suggests targeting RTN3 as a promising therapeutic strategy for MI and related cardiovascular diseases.

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“…Therefore, if a set of cardiovascular biomarkers with high sensitivity, specificity, rapidity, and convenience can be uncovered, it would greatly facilitate real-time and precise detection of cardiovascular aging. Kroemer et al suggest that impaired macroautophagy, loss of protein homeostasis, genomic instability (particularly clonal hematopoiesis of uncertain potential), epigenetic alterations, mitochondrial dysfunction, cellular senescence, dysregulation of neurohormonal signaling, and inflammation are critical contributors to cardiovascular aging [ 1 , 31 ]. However, the aforementioned factors also cause aging in other organs and are not truly specific indicators of cardiovascular aging.…”

Section: Introductionmentioning

confidence: 99%

“…Zhang et al demonstrated that chemokine CCL17 knockdown reduced the expression of vascular fibrosis, elastin fiber breakage, senescence marker p21, and senescence-associated secretory phenotype biomarkers in senescence-induced mice and that CCL17 also attenuated Ang II-induced vascular arteriolar stiffness, systolic-diastolic dysfunction, pathologic vascular remodeling, fibrosis, and the senescence-associated secretory phenotype. Thus, a concept of CCL17 as a novel target in the treatment of cardiovascular aging has now been proposed [ 31 ]. Qu et al’s work revealed that transcription factor FOXO3A reflected a key molecular node in the network of differentially expressed genes (DEGs) that regulate arteriolar vasculature and that FOXO3A expression was downregulated in all six types of senescent vascular wall cells, an important feature of primate arteriolar vasculature senescence [ 29 ].…”

Section: Introductionmentioning

confidence: 99%

Extracellular vesicle-derived TP53BP1, CD34, and PBX1 from human peripheral blood serve as potential biomarkers for the assessment and prediction of vascular aging

Wen,

Chen,

Wang

et al. 2024

Hereditas

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Background Vascular aging is an important pathophysiological basis for the senescence of various organs and systems in the human body, and it is a common pathogenetic trigger for many chronic diseases in the elderly. Methods The extracellular vesicles (EVs) from young and aged umbilical vein endothelial cells were isolated and identified by qPCR the differential expression levels of 47 mRNAs of genes closely related to aging in the two groups. Results There were significant differences in the expression levels of 18 genes (we noted upregulation in PLA2G12A, TP53BP1, CD144, PDE11A, FPGT, SERPINB4, POLD1, and PPFIBP2 and downregulation in ATP2C2, ROBO2, RRM2, GUCY1B1, NAT1-14, VEGFR2, WTAPP1, CD146, DMC1, and GRIK2). Subsequent qPCR identification of the above-mentioned genes in PBMCs and plasma-EVs from the various age groups revealed that the trend in expression levels in peripheral blood plasma-EVs of the different age groups was approximately the same as that in PBMCs. Of these mRNAs, the expression of four genes–PLA2G12A, TP53BP1, OPRL1, and KIAA0895–was commensurate with increasing age. In contradistinction, the expression trend of four genes (CREG1, PBX1, CD34, and SLIT2) was inversely proportional to the increase in age. Finally, by taking their intersection, we determined that the expression of TP53BP1 was upregulated with increasing human age and that CD34 and PBX1 were downregulated with increasing age. Conclusion Our study indicates that human peripheral blood plasma-EV-derived TP53BP1, CD34, and PBX1 potentially comprise a noninvasive biomarker for assessing and predicting vascular aging.

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The chemokine CCL17 is a novel therapeutic target for cardiovascular aging

Cited by 8 publications

References 10 publications

Sirtuin 2 deficiency aggravates ageing-induced vascular remodelling in humans and mice

Sirtuin 2 deficiency aggravates ageing-induced vascular remodelling in humans and mice

Reticulon 3 deficiency ameliorates post‐myocardial infarction heart failure by alleviating mitochondrial dysfunction and inflammation

Extracellular vesicle-derived TP53BP1, CD34, and PBX1 from human peripheral blood serve as potential biomarkers for the assessment and prediction of vascular aging

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