Related Experiment Video
Updated: Sep 20, 2025
Improved Rodent Model of Myocardial Ischemia and Reperfusion Injury
Published on: March 7, 2022
Cationic microbubbles loading shFOXO4/SDF1 rejuvenate the aged heart and alleviate myocardial ischemia-reperfusion
Xingpei Jiang1, Limeng Chao1, Kexun Liu1
1Department of Cardiovascular Surgery, The Second Affiliated Hospital of Harbin Medical University, Harbin, China; Future Medical Laboratory, The Second Affiliated Hospital of Harbin Medical University, Harbin, China.
Insights
This study shows that removing senescent cells and adding mesenchymal stem cells can rejuvenate aging hearts. This dual approach combats cardiac aging and improves outcomes after heart injury.
Area of Science:
- Cardiovascular Research
- Aging Biology
- Regenerative Medicine
Background:
- Aging is a major risk factor for cardiovascular diseases, particularly ischemic heart disease (IHD).
- FOXO4 inhibition removes senescent cells, protecting the aging heart, but may reduce cell density.
- Combining senescent cell removal with mesenchymal stem cell therapy offers synergistic benefits for cardiac aging.
Purpose of the Study:
- To develop a cardiac rejuvenation strategy using ultrasound-targeted microbubble destruction (UTMD) for dual-gene therapy.
- To eliminate cellular senescence and enhance bone marrow-derived mesenchymal stem cell (BMSC) homing in aging hearts.
- To investigate the synergistic effects of FOXO4 inhibition and BMSC replenishment on cardiac aging and ischemia-reperfusion injury.
Main Methods:
- Transcriptomic analysis to identify FOXO4 as a key factor in cardiac aging.
- Knockdown of FOXO4 in aged cardiac fibroblasts (CFs) to reverse senescence.
- Ultrasound-targeted microbubble destruction (UTMD) for delivering shFOXO4/SDF1 to enhance BMSC homing.
- Modeling ischemia-reperfusion injury (MIRI) to assess therapeutic efficacy.
Main Results:
- FOXO4 knockdown in aged CFs reversed senescence and improved oxidative stress resistance when co-cultured with BMSCs.
- UTMD-mediated delivery of shFOXO4/SDF1 enhanced BMSC homing, reducing cardiac aging, oxidative stress, and inflammation.
- Pretreatment in an MIRI model reduced cardiomyocyte apoptosis, promoted neovascularization, decreased infarct size, and improved cardiac function.
Conclusions:
- Combined elimination of senescent cells and enhanced BMSC homing synergistically ameliorates cardiac aging.
- This dual therapy improves post-MIRI prognosis in aging hearts.
- The findings offer novel therapeutic strategies for cardiac aging and related heart diseases.
Abstract:
Aging is a significant risk factor for cardiovascular diseases, with ischemic heart disease (IHD) being the leading cause of cardiovascular-related mortality. Inhibition of FOXO4, which selectively eliminates senescent cells, offers protective effects on the aging myocardium. However, the removal of senescent cells may lead to a reduction in tissue cell density, thereby exacerbating tissue space formation and perivascular fibrosis. Therefore, selectively eliminating senescent cells in the aging heart, while simultaneously replenishing therapeutic bone marrow-derived mesenchymal stem cells (BMSCs), holds substantial therapeutic potential for synergistically combating cardiac aging. This study proposes a promising cardiac rejuvenation strategy using ultrasound-targeted microbubble destruction (UTMD)-mediated delivery of shFOXO4/SDF1 to eliminate cellular senescence and enhance BMSC homing. Transcriptomic analysis identified FOXO4 as a pivotal transcription factor in cardiac aging, with FOXO4 protein predominantly expressed in cardiac fibroblasts (CFs) and vascular endothelial cells in the myocardium of aged rats. Knockdown of FOXO4 in aging CFs reversed cellular senescence, and co-culturing these rejuvenated CFs with BMSCs further enhanced the reversal of senescence and bolstered resistance to oxidative stress. The use of UTMD for delivering shFOXO4/SDF1 in dual-gene therapy significantly enhanced BMSC homing, ameliorating cardiac aging, oxidative stress, and inflammation. In an ischemia-reperfusion injury (MIRI) model, pretreatment with shFOXO4/SDF1 effectively reduced cardiomyocyte apoptosis, promoted neovascularization, reduced infarct size, and improved cardiac function. The combined removal of senescent cells and enhanced BMSC homing synergistically ameliorated cardiac aging and improved post-MIRI prognosis in aging hearts. These findings provide novel insights and potential therapeutic strategies for addressing cardiac aging and age-related heart diseases.
