Calbindin 2 as a Novel Biomarker and Therapeutic Target for Abdominal Aortic Aneurysm: Integrative Analysis of Human Proteomes and Genetics
Background Abdominal aortic aneurysm (AAA) is a clinical life‐threatening issue. No pharmacological treatments are currently approved for the prevention and treatment of AAA. Therefore, identifying novel biomarkers and therapeutic targets is crucial for improving AAA management and outcomes. Methods...
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Wiley
2025-05-01
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| Series: | Journal of the American Heart Association: Cardiovascular and Cerebrovascular Disease |
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| Online Access: | https://www.ahajournals.org/doi/10.1161/JAHA.124.039195 |
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| author | Yulin Bao Jiayi Chen Xudong Han Ye He Tongtong Yang Xinying Shi Jiawen Chen Lingfeng Gu Sibo Wang Liping Xie Hao Wang Liansheng Wang |
| author_facet | Yulin Bao Jiayi Chen Xudong Han Ye He Tongtong Yang Xinying Shi Jiawen Chen Lingfeng Gu Sibo Wang Liping Xie Hao Wang Liansheng Wang |
| author_sort | Yulin Bao |
| collection | DOAJ |
| description | Background Abdominal aortic aneurysm (AAA) is a clinical life‐threatening issue. No pharmacological treatments are currently approved for the prevention and treatment of AAA. Therefore, identifying novel biomarkers and therapeutic targets is crucial for improving AAA management and outcomes. Methods To identify plasma proteins with potential causal effects on AAA, we integrated genetic evidence from proteome‐wide Mendelian randomization, genetic correlation, and colocalization analysis. The role of identified proteins in AAA was further explored through the phenome‐wide association study and mediation analysis. Multiomics data analysis, including bulk RNA sequencing, single‐cell/single‐nucleus RNA sequencing, and spatial transcriptomics, was employed to characterize the expression patterns of these proteins. Experimental validation was performed using an AAA model in apolipoprotein E‐deficient mice infused with angiotensin II. Druggability analysis was conducted to identify drug candidates, which were tested in preclinical mouse models. Results CALB2 (calbindin 2) was identified as having a causal effect on AAA and may influence the progression of AAA through the regulation of lipid metabolism. Multiomics analysis revealed that CALB2 is predominantly expressed in the mesothelial cells of adipose tissues. Inhibition of CALB2 in an AAA mouse model alleviated AAA progression. Druggability analysis identified lenalidomide and genistein as potential therapeutic candidates, and experiments confirmed their efficacy in preventing AAA development. Conclusions This study identifies CALB2 as being associated with an increased risk of AAA and suggests that i might be a novel biomarker and therapeutic molecule for AAA management. Lenalidomide and genistein hold promising potential as treatments for patients with AAA. |
| format | Article |
| id | doaj-art-2126a1e5d6ac495ca429fa57470c57cc |
| institution | DOAJ |
| issn | 2047-9980 |
| language | English |
| publishDate | 2025-05-01 |
| publisher | Wiley |
| record_format | Article |
| series | Journal of the American Heart Association: Cardiovascular and Cerebrovascular Disease |
| spelling | doaj-art-2126a1e5d6ac495ca429fa57470c57cc2025-08-20T03:07:16ZengWileyJournal of the American Heart Association: Cardiovascular and Cerebrovascular Disease2047-99802025-05-0114910.1161/JAHA.124.039195Calbindin 2 as a Novel Biomarker and Therapeutic Target for Abdominal Aortic Aneurysm: Integrative Analysis of Human Proteomes and GeneticsYulin Bao0Jiayi Chen1Xudong Han2Ye He3Tongtong Yang4Xinying Shi5Jiawen Chen6Lingfeng Gu7Sibo Wang8Liping Xie9Hao Wang10Liansheng Wang11Department of Cardiology The First Affiliated Hospital with Nanjing Medical University Nanjing Jiangsu ChinaDepartment of Cardiology The First Affiliated Hospital with Nanjing Medical University Nanjing Jiangsu ChinaDepartment of Cardiology The First Affiliated Hospital with Nanjing Medical University Nanjing Jiangsu ChinaDepartment of Cardiology The First Affiliated Hospital with Nanjing Medical University Nanjing Jiangsu ChinaDepartment of Cardiology The First Affiliated Hospital with Nanjing Medical University Nanjing Jiangsu ChinaDepartment of Cardiology The First Affiliated Hospital with Nanjing Medical University Nanjing Jiangsu ChinaDepartment of Cardiology The First Affiliated Hospital with Nanjing Medical University Nanjing Jiangsu ChinaDepartment of Cardiology The First Affiliated Hospital with Nanjing Medical University Nanjing Jiangsu ChinaDepartment of Cardiology The First Affiliated Hospital with Nanjing Medical University Nanjing Jiangsu ChinaKey Laboratory of Cardiovascular and Cerebrovascular Medicine, Key Laboratory of Targeted Intervention of Cardiovascular Disease, Collaborative Innovation Center for Cardiovascular Disease Translational Medicine Nanjing Medical University Nanjing Jiangsu ChinaDepartment of Cardiology The First Affiliated Hospital with Nanjing Medical University Nanjing Jiangsu ChinaDepartment of Cardiology The First Affiliated Hospital with Nanjing Medical University Nanjing Jiangsu ChinaBackground Abdominal aortic aneurysm (AAA) is a clinical life‐threatening issue. No pharmacological treatments are currently approved for the prevention and treatment of AAA. Therefore, identifying novel biomarkers and therapeutic targets is crucial for improving AAA management and outcomes. Methods To identify plasma proteins with potential causal effects on AAA, we integrated genetic evidence from proteome‐wide Mendelian randomization, genetic correlation, and colocalization analysis. The role of identified proteins in AAA was further explored through the phenome‐wide association study and mediation analysis. Multiomics data analysis, including bulk RNA sequencing, single‐cell/single‐nucleus RNA sequencing, and spatial transcriptomics, was employed to characterize the expression patterns of these proteins. Experimental validation was performed using an AAA model in apolipoprotein E‐deficient mice infused with angiotensin II. Druggability analysis was conducted to identify drug candidates, which were tested in preclinical mouse models. Results CALB2 (calbindin 2) was identified as having a causal effect on AAA and may influence the progression of AAA through the regulation of lipid metabolism. Multiomics analysis revealed that CALB2 is predominantly expressed in the mesothelial cells of adipose tissues. Inhibition of CALB2 in an AAA mouse model alleviated AAA progression. Druggability analysis identified lenalidomide and genistein as potential therapeutic candidates, and experiments confirmed their efficacy in preventing AAA development. Conclusions This study identifies CALB2 as being associated with an increased risk of AAA and suggests that i might be a novel biomarker and therapeutic molecule for AAA management. Lenalidomide and genistein hold promising potential as treatments for patients with AAA.https://www.ahajournals.org/doi/10.1161/JAHA.124.039195abdominal aortic aneurysmcalbindin 2Mendelian randomizationplasma proteinproteogenomic |
| spellingShingle | Yulin Bao Jiayi Chen Xudong Han Ye He Tongtong Yang Xinying Shi Jiawen Chen Lingfeng Gu Sibo Wang Liping Xie Hao Wang Liansheng Wang Calbindin 2 as a Novel Biomarker and Therapeutic Target for Abdominal Aortic Aneurysm: Integrative Analysis of Human Proteomes and Genetics Journal of the American Heart Association: Cardiovascular and Cerebrovascular Disease abdominal aortic aneurysm calbindin 2 Mendelian randomization plasma protein proteogenomic |
| title | Calbindin 2 as a Novel Biomarker and Therapeutic Target for Abdominal Aortic Aneurysm: Integrative Analysis of Human Proteomes and Genetics |
| title_full | Calbindin 2 as a Novel Biomarker and Therapeutic Target for Abdominal Aortic Aneurysm: Integrative Analysis of Human Proteomes and Genetics |
| title_fullStr | Calbindin 2 as a Novel Biomarker and Therapeutic Target for Abdominal Aortic Aneurysm: Integrative Analysis of Human Proteomes and Genetics |
| title_full_unstemmed | Calbindin 2 as a Novel Biomarker and Therapeutic Target for Abdominal Aortic Aneurysm: Integrative Analysis of Human Proteomes and Genetics |
| title_short | Calbindin 2 as a Novel Biomarker and Therapeutic Target for Abdominal Aortic Aneurysm: Integrative Analysis of Human Proteomes and Genetics |
| title_sort | calbindin 2 as a novel biomarker and therapeutic target for abdominal aortic aneurysm integrative analysis of human proteomes and genetics |
| topic | abdominal aortic aneurysm calbindin 2 Mendelian randomization plasma protein proteogenomic |
| url | https://www.ahajournals.org/doi/10.1161/JAHA.124.039195 |
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