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Effects of intracardiac delivery of aldehyde dehydrogenase 2 gene in myocardial salvage

Gene Therapy volume 30, pages 115–121 (2023)Cite this article

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Abstract

Intrinsic activity of aldehyde dehydrogenase (ALDH)2, a cardiac mitochondrial enzyme, is vital in detoxifying 4-hydroxy-2-nonenal (4HNE) like cellular reactive carbonyl species (RCS) and thereby conferring cardiac protection against pathological stress. It was also known that a single point mutation (E487K) in ALDH2 (prevalent in East Asians) known as ALDH2*2 reduces its activity intrinsically and was associated with increased cardiovascular diseases. We and others have shown that ALDH2 activity is reduced in several pathologies in WT animals as well. Thus, exogenous augmentation of ALDH2 activity is a good strategy to protect the myocardium from pathologies. In this study, we will test the efficacy of intracardiac injections of the ALDH2 gene in mice. We injected both wild type (WT) and ALDH2*2 knock-in mutant mice with ALDH2 constructs, AAv9-cTNT-hALDH2-HA tag-P2A-eGFP or their control constructs, AAv9-cTNT-eGFP. We found that intracardiac ALDH2 gene transfer increased myocardial levels of ALDH2 compared to GFP alone after 1 and 3 weeks. When we subjected the hearts of these mice to 30 min global ischemia and 90 min reperfusion (I-R) using the Langendorff perfusion system, we found reduced infarct size in the hearts of mice with ALDH2 gene vs GFP alone. A single time injection has shown increased myocardial ALDH2 activity for at least 3 weeks and reduced myocardial 4HNE adducts and infarct size along with increased contractile function of the hearts while subjected to I-R. Thus, ALDH2 overexpression protected the myocardium from I-R injury by reducing 4HNE protein adducts implicating increased 4HNE detoxification by ALDH2. In conclusion, intracardiac ALDH2 gene transfer is an effective strategy to protect the myocardium from pathological insults.

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Fig. 1: Map of ALDH2 construct.
Fig. 2: Immunofluorescence imaging of Hoechst dye from the injection, GFP from the construct and ALDH2 from staining show effective transduction.
Fig. 3: Cardiac ALDH2 levels after 1 and 3 weeks of intracardiac transfection.
Fig. 4: Cardiac ALDH2 levels, ALDH2 activity and 4HNE protein adducts in the WT and ALDH2*2 mutant mouse hearts subjected to global ischemia-reperfusion injury after AAV9-ALDH2-GFP and AAV9-GFP transfections.
Fig. 5: Myocardial infarct size measurements of WT and ALDH2*2 mutant mouse hearts subjected to global ischemia-reperfusion injury after AAV9-ALDH2-GFP and AAV9-GFP transfections.
Fig. 6: Changes in cardiac functional indices of WT and ALDH2*2 mutant mouse hearts subjected to global ischemia-reperfusion injury after AAV9-ALDH2-GFP and AAV9-GFP transfections.

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Acknowledgements

We thank Durga Dham and Saswat Saravanan for their English editing.

Funding

SSP was supported by a grant from the National Heart, Lung, and Blood Institute 1R56HL131891-01A1, 1R01HL139877-01A1, and an internal grant from Henry Ford Health System A10249.

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Authors and Affiliations

  1. Division of Hypertension and Vascular Research, Department of Internal Medicine, Henry Ford Health System, Detroit, MI, 48202, USA

    Guodong Pan, Bipradas Roy, Pamela Harding & Suresh Selvaraj Palaniyandi

  2. Department of Physiology, Wayne State University, Detroit, MI, 48202, USA

    Guodong Pan, Bipradas Roy, Pamela Harding & Suresh Selvaraj Palaniyandi

  3. Vector Core, Biomedical Research Core Facilities, University of Michigan Medical School, Ann Arbor, MI, 48109, USA

    Thomas Lanigan & Roland Hilgarth

  4. Department of Cardiovascular Sciences, Houston Methodist Research Institute, Houston, TX, 77030, USA

    Rajarajan A. Thandavarayan

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  1. Guodong Pan
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Contributions

GP conducted the study, collected, analyzed, and organized the data. BR contributed to the data collection. TL and RH contributed to construct design and production and quality control. RAT contributed to manuscript editing. SSP contributed to overall project conception, experimental design, data analysis and organization and then, manuscript writing/editing and finalization. All authors reviewed the manuscript.

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Correspondence to Suresh Selvaraj Palaniyandi.

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Pan, G., Roy, B., Harding, P. et al. Effects of intracardiac delivery of aldehyde dehydrogenase 2 gene in myocardial salvage. Gene Ther 30, 115–121 (2023). https://doi.org/10.1038/s41434-022-00345-2

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