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Despite accounting for nearly 50% of all HF cases, heart failure with a preserved ejection fraction (HFpEF) remains challenging to treat. Common pathophysiological mechanisms in HFpEF include oxidative stress, microvascular dysfunction, and chronic unresolved inflammation. Our lab focuses on oxidative stress-mediated cellular dysfunction, particularly the toxic effects of lipid peroxidation products like 4-hydroxy-2-nonenal (4HNE). Aldehyde dehydrogenase 2 (ALDH2), a mitochondrial enzyme, plays a vital role in detoxifying 4HNE and thereby protecting the heart against pathological stress. ALDH2 activity is reduced in various metabolic stress-mediated cardiac pathologies. The dysfunction of coronary vascular endothelial cells (CVECs) is critical in initiating HFpEF development. Thus, we hypothesized that ectopic overexpression of ALDH2 in CVECs could mitigate metabolic stress-induced HFpEF pathogenesis. In this study, we tested the efficacy of intracardiac injections of the ALDH2 gene into CVECs in db\/db mice\u2014a model of obesity-induced type 2 diabetes mellitus (T2DM)\u2014and their controls, db\/m mice, by injection with ALDH2 constructs (AAV9-VE-cadherin-hALDH2-HA tag-P2A) or control constructs (AAV9-VE-cadherin-HA tag-P2A-eGFP). We found that intracardiac ALDH2 gene transfer increased ALDH2 levels specifically in CVECs compared to other myocardial cells. Additionally, we observed increased ALDH2 levels and activity, along with decreased 4HNE adducts, in the hearts of mice receiving ALDH2 gene transfer compared to control GFP transfer. Furthermore, ALDH2 gene transfer to CVECs improved diastolic function compared to GFP control alone. In conclusion, ectopic ALDH2 expression in CVECs can contribute, at least partially, to the amelioration of HFpEF.<\/jats:p>","DOI":"10.3390\/biom15071029","type":"journal-article","created":{"date-parts":[[2025,7,16]],"date-time":"2025-07-16T15:48:22Z","timestamp":1752680902000},"page":"1029","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Targeted Overexpression of Mitochondrial ALDH2 in Coronary Endothelial Cells Mitigates HFpEF in a Diabetic Mouse Model"],"prefix":"10.3390","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0594-4492","authenticated-orcid":false,"given":"Guodong","family":"Pan","sequence":"first","affiliation":[{"name":"Division of Hypertension and Vascular Research, Department of Internal Medicine, Henry Ford Health System, Detroit, MI 48202, USA"},{"name":"Department of Physiology, Wayne State University, Detroit, MI 48202, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6472-951X","authenticated-orcid":false,"given":"Bipradas","family":"Roy","sequence":"additional","affiliation":[{"name":"Division of Hypertension and Vascular Research, Department of Internal Medicine, Henry Ford Health System, Detroit, MI 48202, USA"},{"name":"Department of Physiology, Wayne State University, Detroit, MI 48202, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0007-6453-3112","authenticated-orcid":false,"given":"Emmanuel Oppong","family":"Yeboah","sequence":"additional","affiliation":[{"name":"Division of Hypertension and Vascular Research, Department of Internal Medicine, Henry Ford Health System, Detroit, MI 48202, USA"},{"name":"Department of Physiology, Wayne State University, Detroit, MI 48202, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thomas","family":"Lanigan","sequence":"additional","affiliation":[{"name":"Vector Core, Biomedical Research Core Facilities, University of Michigan Medical School, Ann Arbor, MI 48109, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Roland","family":"Hilgarth","sequence":"additional","affiliation":[{"name":"Vector Core, Biomedical Research Core Facilities, University of Michigan Medical School, Ann Arbor, MI 48109, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8452-2903","authenticated-orcid":false,"given":"Rajarajan A.","family":"Thandavarayan","sequence":"additional","affiliation":[{"name":"Department of Cardiovascular Sciences, Houston Methodist Research Institute, Houston, TX 77030, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5583-8092","authenticated-orcid":false,"given":"Michael C.","family":"Petriello","sequence":"additional","affiliation":[{"name":"Institute of Environmental Health Sciences, Wayne State University, Detroit, MI 48202, USA"},{"name":"Department of Pharmacology, Wayne State University, Detroit, MI 48202, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7123-829X","authenticated-orcid":false,"given":"Shailendra","family":"Giri","sequence":"additional","affiliation":[{"name":"Department of Neurology, Henry Ford Health, Detroit, MI 48202, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Suresh Selvaraj","family":"Palaniyandi","sequence":"additional","affiliation":[{"name":"Division of Hypertension and Vascular Research, Department of Internal Medicine, Henry Ford Health System, Detroit, MI 48202, USA"},{"name":"Department of Physiology, Wayne State University, Detroit, MI 48202, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,7,16]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1412","DOI":"10.1016\/j.cardfail.2023.07.006","article-title":"Heart Failure Epidemiology and Outcomes Statistics: A Report of the Heart Failure Society of America","volume":"29","author":"Bozkurt","year":"2023","journal-title":"J. Card. Fail."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"591","DOI":"10.1038\/nrcardio.2017.65","article-title":"Epidemiology of heart failure with preserved ejection fraction","volume":"14","author":"Dunlay","year":"2017","journal-title":"Nat. Rev. Cardiol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"770","DOI":"10.1016\/j.jacbts.2017.07.013","article-title":"Murine Models of Heart Failure with Preserved Ejection Fraction: A \u201cFishing Expedition\u201d","volume":"2","author":"Backman","year":"2017","journal-title":"JACC Basic. Transl. Sci."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"71","DOI":"10.1186\/s12933-025-02612-z","article-title":"Challenges in the diagnosis of heart failure with preserved ejection fraction in individuals with obesity","volume":"24","author":"Chin","year":"2025","journal-title":"Cardiovasc. Diabetol."},{"key":"ref_5","doi-asserted-by":"crossref","unstructured":"Abudureyimu, M., Luo, X., Wang, X., Sowers, J.R., Wang, W., Ge, J., Ren, J., and Zhang, Y. (2022). Heart failure with preserved ejection fraction (HFpEF) in type 2 diabetes mellitus: From pathophysiology to therapeutics. J. Mol. Cell Biol., 14.","DOI":"10.1093\/jmcb\/mjac028"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"311","DOI":"10.1016\/j.bbalip.2009.09.023","article-title":"Lipotoxicity in the heart","volume":"1801","author":"Wende","year":"2010","journal-title":"Biochim. Biophys. Acta"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"82","DOI":"10.1016\/j.coph.2020.08.015","article-title":"Disruption of energy utilization in diabetic cardiomyopathy; a mini review","volume":"54","author":"Nirengi","year":"2020","journal-title":"Curr. Opin. Pharmacol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"1208","DOI":"10.1161\/CIRCRESAHA.125.325489","article-title":"Contributions of Noncardiac Organ-Heart Immune Crosstalk and Somatic Mosaicism to Heart Failure: Current Knowledge and Perspectives","volume":"136","author":"Kallikourdis","year":"2025","journal-title":"Circ. Res."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"312","DOI":"10.1016\/j.jchf.2015.10.007","article-title":"Myocardial Microvascular Inflammatory Endothelial Activation in Heart Failure with Preserved Ejection Fraction","volume":"4","author":"Franssen","year":"2016","journal-title":"JACC Heart Fail."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"251","DOI":"10.3109\/10715762.2013.864761","article-title":"Regulation and therapeutic strategies of 4-hydroxy-2-nonenal metabolism in heart disease","volume":"48","author":"Mali","year":"2014","journal-title":"Free Radic. Res."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"547","DOI":"10.1080\/10715762.2020.1866756","article-title":"4-Hydroxy-2-nonenal, a lipid peroxidation product, as a biomarker in diabetes and its complications: Challenges and opportunities","volume":"55","author":"Dham","year":"2021","journal-title":"Free Radic. Res."},{"key":"ref_12","doi-asserted-by":"crossref","unstructured":"Pan, G., Munukutla, S., Kar, A., Gardinier, J., Thandavarayan, R.A., and Palaniyandi, S.S. (2018). Type-2 diabetic aldehyde dehydrogenase 2 mutant mice (ALDH 2*2) exhibiting heart failure with preserved ejection fraction phenotype can be determined by exercise stress echocardiography. PLoS ONE, 13.","DOI":"10.1371\/journal.pone.0203581"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"e021140","DOI":"10.1161\/JAHA.121.021140","article-title":"Diabetic Aldehyde Dehydrogenase 2 Mutant (ALDH2*2) Mice Are More Susceptible to Cardiac Ischemic-Reperfusion Injury Due to 4-Hydroxy-2-Nonenal Induced Coronary Endothelial Cell Damage","volume":"10","author":"Pan","year":"2021","journal-title":"J. Am. Heart Assoc."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"e22440","DOI":"10.1096\/fj.202200498R","article-title":"Aldehyde dehydrogenase 2 augments adiponectin signaling in coronary angiogenesis in HFpEF associated with diabetes","volume":"36","author":"Roy","year":"2022","journal-title":"FASEB J."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"610","DOI":"10.1177\/1535370213520109","article-title":"Impairment of aldehyde dehydrogenase-2 by 4-hydroxy-2-nonenal adduct formation and cardiomyocyte hypertrophy in mice fed a high-fat diet and injected with low-dose streptozotocin","volume":"239","author":"Mali","year":"2014","journal-title":"Exp. Biol. Med."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"89","DOI":"10.1016\/j.freeradbiomed.2012.11.010","article-title":"Aldehyde dehydrogenases in cellular responses to oxidative\/electrophilic stress","volume":"56","author":"Singh","year":"2013","journal-title":"Free Radic. Biol. Med."},{"key":"ref_17","doi-asserted-by":"crossref","unstructured":"Gao, J., Hao, Y., Piao, X., and Gu, X. (2022). Aldehyde Dehydrogenase 2 as a Therapeutic Target in Oxidative Stress-Related Diseases: Post-Translational Modifications Deserve More Attention. Int. J. Mol. Sci., 23.","DOI":"10.3390\/ijms23052682"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"C537","DOI":"10.1152\/ajpcell.00101.2016","article-title":"4-Hydroxy-2-nonenal: A critical target in oxidative stress?","volume":"311","author":"Breitzig","year":"2016","journal-title":"Am. J. Physiol. Cell Physiol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"1493","DOI":"10.1126\/science.1158554","article-title":"Activation of aldehyde dehydrogenase-2 reduces ischemic damage to the heart","volume":"321","author":"Chen","year":"2008","journal-title":"Science"},{"key":"ref_20","doi-asserted-by":"crossref","unstructured":"Ji, W., Wei, S., Hao, P., Xing, J., Yuan, Q., Wang, J., Xu, F., and Chen, Y. (2016). Aldehyde Dehydrogenase 2 Has Cardioprotective Effects on Myocardial Ischaemia\/Reperfusion Injury via Suppressing Mitophagy. Front. Pharmacol., 7.","DOI":"10.3389\/fphar.2016.00101"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"2175","DOI":"10.18632\/oncotarget.6814","article-title":"Aldehyde dehydrogenase 2 activation in aged heart improves the autophagy by reducing the carbonyl modification on SIRT1","volume":"7","author":"Wu","year":"2016","journal-title":"Oncotarget"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"9088","DOI":"10.1073\/pnas.1510757112","article-title":"ALDH2(E487K) mutation increases protein turnover and promotes murine hepatocarcinogenesis","volume":"112","author":"Jin","year":"2015","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"e24","DOI":"10.15420\/cfr.2022.12","article-title":"Microvascular Dysfunction in Heart Failure with Preserved Ejection Fraction: Pathophysiology, Assessment, Prevalence and Prognosis","volume":"8","author":"Bilak","year":"2022","journal-title":"Card. Fail. Rev."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"550","DOI":"10.1161\/CIRCULATIONAHA.114.009625","article-title":"Coronary microvascular rarefaction and myocardial fibrosis in heart failure with preserved ejection fraction","volume":"131","author":"Mohammed","year":"2015","journal-title":"Circulation"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"263","DOI":"10.1016\/j.jacc.2013.02.092","article-title":"A novel paradigm for heart failure with preserved ejection fraction: Comorbidities drive myocardial dysfunction and remodeling through coronary microvascular endothelial inflammation","volume":"62","author":"Paulus","year":"2013","journal-title":"J. Am. Coll. Cardiol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"315","DOI":"10.1097\/FJC.0000000000000719","article-title":"Sirtuin 3, Endothelial Metabolic Reprogramming, and Heart Failure with Preserved Ejection Fraction","volume":"74","author":"Zeng","year":"2019","journal-title":"J. Cardiovasc. Pharmacol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"290","DOI":"10.1002\/cbf.3468","article-title":"Aldehyde dehydrogenase 2 inhibition potentiates 4-hydroxy-2-nonenal induced decrease in angiogenesis of coronary endothelial cells","volume":"38","author":"Roy","year":"2020","journal-title":"Cell Biochem. Funct."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"104133","DOI":"10.1016\/j.mvr.2021.104133","article-title":"A role for aldehyde dehydrogenase (ALDH) 2 in angiotensin II-mediated decrease in angiogenesis of coronary endothelial cells","volume":"135","author":"Roy","year":"2021","journal-title":"Microvasc. Res."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"106762","DOI":"10.1016\/j.vph.2020.106762","article-title":"4-hydroxy-2-nonenal decreases coronary endothelial cell migration: Potentiation by aldehyde dehydrogenase 2 inhibition","volume":"131","author":"Roy","year":"2020","journal-title":"Vasc. Pharmacol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"39","DOI":"10.1007\/s00395-020-0798-y","article-title":"Microvascular and lymphatic dysfunction in HFpEF and its associated comorbidities","volume":"115","author":"Cuijpers","year":"2020","journal-title":"Basic. Res. Cardiol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"351","DOI":"10.1038\/s41586-019-1100-z","article-title":"Nitrosative stress drives heart failure with preserved ejection fraction","volume":"568","author":"Schiattarella","year":"2019","journal-title":"Nature"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"423","DOI":"10.1093\/cvr\/cvaa217","article-title":"Metabolic inflammation in heart failure with preserved ejection fraction","volume":"117","author":"Schiattarella","year":"2021","journal-title":"Cardiovasc. Res."},{"key":"ref_33","doi-asserted-by":"crossref","unstructured":"Mali, V.R., Pan, G., Deshpande, M., Thandavarayan, R.A., Xu, J., Yang, X.P., and Palaniyandi, S.S. (2016). Cardiac Mitochondrial Respiratory Dysfunction and Tissue Damage in Chronic Hyperglycemia Correlate with Reduced Aldehyde Dehydrogenase-2 Activity. PLoS ONE, 11.","DOI":"10.1371\/journal.pone.0163158"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.vph.2017.05.005","article-title":"Oxidative stress and reactive oxygen species in endothelial dysfunction associated with cardiovascular and metabolic diseases","volume":"100","author":"Incalza","year":"2018","journal-title":"Vasc. Pharmacol."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"13","DOI":"10.1007\/s12012-018-9493-8","article-title":"Endothelial Cells: From Dysfunction Mechanism to Pharmacological Effect in Cardiovascular Disease","volume":"19","author":"Haybar","year":"2019","journal-title":"Cardiovasc. Toxicol."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"128","DOI":"10.1016\/j.freeradbiomed.2019.11.023","article-title":"The relevance of pathophysiological alterations in redox signaling of 4-hydroxynonenal for pharmacological therapies of major stress-associated diseases","volume":"157","author":"Jaganjac","year":"2020","journal-title":"Free Radic. Biol. Med."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"501","DOI":"10.1016\/j.jacbts.2022.11.005","article-title":"Obesity-Induced Coronary Microvascular Disease Is Prevented by iNOS Deletion and Reversed by iNOS Inhibition","volume":"8","author":"Shah","year":"2023","journal-title":"JACC Basic. Transl. Sci."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"3434","DOI":"10.1093\/cvr\/cvac120","article-title":"Obesity and heart failure with preserved ejection fraction: New insights and pathophysiological targets","volume":"118","author":"Borlaug","year":"2023","journal-title":"Cardiovasc. Res."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"e006082","DOI":"10.1161\/JAHA.117.006082","article-title":"Body Mass Index Is Associated with Microvascular Endothelial Dysfunction in Patients With Treated Metabolic Risk Factors and Suspected Coronary Artery Disease","volume":"6","author":"Janssens","year":"2017","journal-title":"J. Am. Heart Assoc."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"61","DOI":"10.1186\/s12933-017-0544-4","article-title":"Dipeptidyl peptidase-4 (DPP-4) inhibition with linagliptin reduces western diet-induced myocardial TRAF3IP2 expression, inflammation and fibrosis in female mice","volume":"16","author":"Aroor","year":"2017","journal-title":"Cardiovasc. Diabetol."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"H203","DOI":"10.1152\/ajpheart.00038.2023","article-title":"Characterization of a robust mouse model of heart failure with preserved ejection fraction","volume":"325","author":"Matsiukevich","year":"2023","journal-title":"Am. J. Physiol. Heart Circ. Physiol."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"H934","DOI":"10.1152\/ajpheart.00238.2018","article-title":"Characterization of a mouse model of obesity-related fibrotic cardiomyopathy that recapitulates features of human heart failure with preserved ejection fraction","volume":"315","author":"Alex","year":"2018","journal-title":"Am. J. Physiol. Heart Circ. Physiol."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"201","DOI":"10.1016\/S0165-6147(00)01676-X","article-title":"FGF and VEGF function in angiogenesis: Signalling pathways, biological responses and therapeutic inhibition","volume":"22","author":"Cross","year":"2001","journal-title":"Trends Pharmacol. Sci."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"2387","DOI":"10.2174\/13816128113199990474","article-title":"Dipeptidyl-peptidase 4 inhibition: Linking metabolic control to cardiovascular protection","volume":"20","author":"Avogaro","year":"2014","journal-title":"Curr. Pharm. Des."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"319","DOI":"10.1016\/j.redox.2013.04.001","article-title":"Effects of 4-hydroxynonenal on vascular endothelial and smooth muscle cell redox signaling and function in health and disease","volume":"1","author":"Chapple","year":"2013","journal-title":"Redox Biol."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"602","DOI":"10.1016\/j.jacc.2018.11.033","article-title":"Heart Failure with Preserved Ejection Fraction and Diabetes: JACC State-of-the-Art Review","volume":"73","author":"McHugh","year":"2019","journal-title":"J. Am. Coll. Cardiol."},{"key":"ref_47","doi-asserted-by":"crossref","unstructured":"Jasinska-Stroschein, M. (2023). The current state of preclinical modeling of human diabetic cardiomyopathy using rodents. Biomed. Pharmacother., 168.","DOI":"10.1016\/j.biopha.2023.115843"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"131","DOI":"10.1016\/j.jacc.2016.10.058","article-title":"Diabetes Mellitus-Induced Microvascular Destabilization in the Myocardium","volume":"69","author":"Hinkel","year":"2017","journal-title":"J. Am. Coll. Cardiol."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"157","DOI":"10.1089\/humc.2017.070","article-title":"Use of Adeno-Associated Virus Vector for Cardiac Gene Delivery in Large-Animal Surgical Models of Heart Failure","volume":"28","author":"Katz","year":"2017","journal-title":"Hum. Gene Ther. Clin. Dev."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"7875","DOI":"10.1128\/JVI.00649-08","article-title":"Adeno-associated virus vector genomes persist as episomal chromatin in primate muscle","volume":"82","author":"Nowrouzi","year":"2008","journal-title":"J. Virol."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"23","DOI":"10.1182\/blood-2013-01-306647","article-title":"Immune responses to AAV vectors: Overcoming barriers to successful gene therapy","volume":"122","author":"Mingozzi","year":"2013","journal-title":"Blood"},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"1441","DOI":"10.1002\/ejhf.2596","article-title":"A pilot clinical trial of cell therapy in heart failure with preserved ejection fraction","volume":"24","author":"Vrtovec","year":"2022","journal-title":"Eur. J. Heart Fail."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"165","DOI":"10.1161\/CIRCRESAHA.112.276519","article-title":"Effects of intracoronary CD34+ stem cell transplantation in nonischemic dilated cardiomyopathy patients: 5-year follow-up","volume":"112","author":"Vrtovec","year":"2013","journal-title":"Circ. Res."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"115","DOI":"10.1038\/s41434-022-00345-2","article-title":"Effects of intracardiac delivery of aldehyde dehydrogenase 2 gene in myocardial salvage","volume":"30","author":"Pan","year":"2023","journal-title":"Gene Ther."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"120","DOI":"10.1161\/CIRCULATIONAHA.120.050498","article-title":"Myocardial Gene Expression Signatures in Human Heart Failure with Preserved Ejection Fraction","volume":"143","author":"Hahn","year":"2021","journal-title":"Circulation"},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"59","DOI":"10.1089\/hgtb.2012.243","article-title":"Pre-existing anti-adeno-associated virus antibodies as a challenge in AAV gene therapy","volume":"24","author":"Joergensen","year":"2013","journal-title":"Hum. Gene Ther. Methods"},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"194ra192","DOI":"10.1126\/scitranslmed.3005795","article-title":"Overcoming preexisting humoral immunity to AAV using capsid decoys","volume":"5","author":"Mingozzi","year":"2013","journal-title":"Sci. Transl. Med."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"952","DOI":"10.1016\/j.ymthe.2024.02.002","article-title":"High-dose systemic adeno-associated virus vector administration causes liver and sinusoidal endothelial cell injury","volume":"32","author":"Hordeaux","year":"2024","journal-title":"Mol. Ther."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"60","DOI":"10.1038\/s41434-023-00405-1","article-title":"Adeno-associated virus vectors and neurotoxicity-lessons from preclinical and human studies","volume":"32","author":"Stone","year":"2025","journal-title":"Gene Ther."}],"container-title":["Biomolecules"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2218-273X\/15\/7\/1029\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,9]],"date-time":"2025-10-09T18:10:57Z","timestamp":1760033457000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2218-273X\/15\/7\/1029"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,7,16]]},"references-count":59,"journal-issue":{"issue":"7","published-online":{"date-parts":[[2025,7]]}},"alternative-id":["biom15071029"],"URL":"https:\/\/doi.org\/10.3390\/biom15071029","relation":{},"ISSN":["2218-273X"],"issn-type":[{"value":"2218-273X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,7,16]]}}}