Constance Delwarde, Diego Pestana, Taku Kasai, Shio Kuraoka, Yuto Nakamura, Takeshi Okada, Julius Decano, Ge Rile, Andrew Mlynarchik, Katelyn Perez, Alesandra Campedelli, Sarvesh Chelvanambi, Sasha Singh, Elena Aikawa, Masanori Aikawa
{"title":"动脉粥样硬化小鼠模型中的adp核糖基化:血脂异常与心血管疾病炎症之间的潜在新联系","authors":"Constance Delwarde, Diego Pestana, Taku Kasai, Shio Kuraoka, Yuto Nakamura, Takeshi Okada, Julius Decano, Ge Rile, Andrew Mlynarchik, Katelyn Perez, Alesandra Campedelli, Sarvesh Chelvanambi, Sasha Singh, Elena Aikawa, Masanori Aikawa","doi":"10.1016/j.acvd.2025.03.004","DOIUrl":null,"url":null,"abstract":"<div><h3>Introduction</h3><div>Inflammation and lipid accumulation are major features of atherosclerosis, a leading cause of death and morbidity worldwide. Our previous study recognized ADP-ribosylation, a post-translational modification, as a novel regulator of macrophage activation. We also have established mass spectrometry-based ADP-ribosylation proteomics. Using this technology, we evaluated the completely uncharacterized role of ADP-ribosylation in atherogenesis.</div><div>Objectif We hypothesized that ADP-ribosylated proteins circulate from liver, accumulate in aorta and promote atherogenesis.</div></div><div><h3>Method</h3><div>We harvested the aorta, liver, and plasma of LDL receptor-deficient (Ldlr-/-) mice that were on a regular chow or high-fat diet for 3 or 6 months (<em>n</em> <!-->=<!--> <!-->40/condition).</div></div><div><h3>Results</h3><div>To increase ADP-ribosyl peptide signals in the aorta, we applied our novel recently optimized ion mobility mass spectrometry strategy to generate ADP-ribosylation proteomics data. We analyzed 160 mice aortas and identified 3 APOA1 and 3 APOE ADP-ribosylated peptides in both the aorta and the liver (<span><span>Fig. 1</span></span> A). In addition, these peptides were differentially abundant in the aorta of HFD-fed mice, compared to controls (i.e, APOA1 ARPALEDLR peptide relative abundance [<span><span>Fig. 1</span></span> B]). Using the same mouse plasma, we then validated the presence of ADP-ribosylated APOA1 and ADP-ribosylated APOE in HDL and chylomicron/VLDL/LDL fractions (Western blot), respectively. This finding indicates that classical apolipoproteins circulate as ADP-ribosylated forms, representing a completely novel class of modified apolipoproteins. Immunohistochemistry confirmed the enrichment of aortic lesions in macrophages and ADP-ribosylation signal (5-fold increase, <em>P</em> <!-->=<!--> <!-->0.0006).</div></div><div><h3>Conclusion</h3><div>This work provides the first in vivo evidence that ADP-ribosylation occurs in atherosclerotic lesions, which may originate from the liver via circulating blood (<span><span>Fig. 1</span></span>C). Future studies will examine whether ADP-ribosylation of apolipoproteins, specifically APOA1, alters anti-atherogenic functions of HDL.</div></div>","PeriodicalId":55472,"journal":{"name":"Archives of Cardiovascular Diseases","volume":"118 6","pages":"Page S172"},"PeriodicalIF":2.3000,"publicationDate":"2025-05-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"ADP-ribosylation in a mouse model of atherosclerosis: A potential novel link between dyslipidemia and inflammation in cardiovascular disease\",\"authors\":\"Constance Delwarde, Diego Pestana, Taku Kasai, Shio Kuraoka, Yuto Nakamura, Takeshi Okada, Julius Decano, Ge Rile, Andrew Mlynarchik, Katelyn Perez, Alesandra Campedelli, Sarvesh Chelvanambi, Sasha Singh, Elena Aikawa, Masanori Aikawa\",\"doi\":\"10.1016/j.acvd.2025.03.004\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<div><h3>Introduction</h3><div>Inflammation and lipid accumulation are major features of atherosclerosis, a leading cause of death and morbidity worldwide. Our previous study recognized ADP-ribosylation, a post-translational modification, as a novel regulator of macrophage activation. We also have established mass spectrometry-based ADP-ribosylation proteomics. Using this technology, we evaluated the completely uncharacterized role of ADP-ribosylation in atherogenesis.</div><div>Objectif We hypothesized that ADP-ribosylated proteins circulate from liver, accumulate in aorta and promote atherogenesis.</div></div><div><h3>Method</h3><div>We harvested the aorta, liver, and plasma of LDL receptor-deficient (Ldlr-/-) mice that were on a regular chow or high-fat diet for 3 or 6 months (<em>n</em> <!-->=<!--> <!-->40/condition).</div></div><div><h3>Results</h3><div>To increase ADP-ribosyl peptide signals in the aorta, we applied our novel recently optimized ion mobility mass spectrometry strategy to generate ADP-ribosylation proteomics data. We analyzed 160 mice aortas and identified 3 APOA1 and 3 APOE ADP-ribosylated peptides in both the aorta and the liver (<span><span>Fig. 1</span></span> A). In addition, these peptides were differentially abundant in the aorta of HFD-fed mice, compared to controls (i.e, APOA1 ARPALEDLR peptide relative abundance [<span><span>Fig. 1</span></span> B]). Using the same mouse plasma, we then validated the presence of ADP-ribosylated APOA1 and ADP-ribosylated APOE in HDL and chylomicron/VLDL/LDL fractions (Western blot), respectively. This finding indicates that classical apolipoproteins circulate as ADP-ribosylated forms, representing a completely novel class of modified apolipoproteins. 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ADP-ribosylation in a mouse model of atherosclerosis: A potential novel link between dyslipidemia and inflammation in cardiovascular disease
Introduction
Inflammation and lipid accumulation are major features of atherosclerosis, a leading cause of death and morbidity worldwide. Our previous study recognized ADP-ribosylation, a post-translational modification, as a novel regulator of macrophage activation. We also have established mass spectrometry-based ADP-ribosylation proteomics. Using this technology, we evaluated the completely uncharacterized role of ADP-ribosylation in atherogenesis.
Objectif We hypothesized that ADP-ribosylated proteins circulate from liver, accumulate in aorta and promote atherogenesis.
Method
We harvested the aorta, liver, and plasma of LDL receptor-deficient (Ldlr-/-) mice that were on a regular chow or high-fat diet for 3 or 6 months (n = 40/condition).
Results
To increase ADP-ribosyl peptide signals in the aorta, we applied our novel recently optimized ion mobility mass spectrometry strategy to generate ADP-ribosylation proteomics data. We analyzed 160 mice aortas and identified 3 APOA1 and 3 APOE ADP-ribosylated peptides in both the aorta and the liver (Fig. 1 A). In addition, these peptides were differentially abundant in the aorta of HFD-fed mice, compared to controls (i.e, APOA1 ARPALEDLR peptide relative abundance [Fig. 1 B]). Using the same mouse plasma, we then validated the presence of ADP-ribosylated APOA1 and ADP-ribosylated APOE in HDL and chylomicron/VLDL/LDL fractions (Western blot), respectively. This finding indicates that classical apolipoproteins circulate as ADP-ribosylated forms, representing a completely novel class of modified apolipoproteins. Immunohistochemistry confirmed the enrichment of aortic lesions in macrophages and ADP-ribosylation signal (5-fold increase, P = 0.0006).
Conclusion
This work provides the first in vivo evidence that ADP-ribosylation occurs in atherosclerotic lesions, which may originate from the liver via circulating blood (Fig. 1C). Future studies will examine whether ADP-ribosylation of apolipoproteins, specifically APOA1, alters anti-atherogenic functions of HDL.
期刊介绍:
The Journal publishes original peer-reviewed clinical and research articles, epidemiological studies, new methodological clinical approaches, review articles and editorials. Topics covered include coronary artery and valve diseases, interventional and pediatric cardiology, cardiovascular surgery, cardiomyopathy and heart failure, arrhythmias and stimulation, cardiovascular imaging, vascular medicine and hypertension, epidemiology and risk factors, and large multicenter studies. Archives of Cardiovascular Diseases also publishes abstracts of papers presented at the annual sessions of the Journées Européennes de la Société Française de Cardiologie and the guidelines edited by the French Society of Cardiology.