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CCR2 inhibitor strengthens the adiponectin effects against myocardial injury after infarction
Yue Zheng1,2,3,4,5,6, Wenqing Gao1,2,3,4,5,6, Bingcai Qi1,4,5,6
1School of Medicine, Nankai University, Tianjin, China.
Abstract:
Little evidence demonstrated the effects of nitric oxide (NO) hydrogel with adipocytes in vivo. We aimed to investigate the effects of adiponectin (ADPN) and CCR2 antagonist on cardiac functions and macrophage phenotypes after myocardial infarction (MI) using chitosan caged nitric oxide donor (CSNO) patch with adipocytes. 3T3-L1 cell line was induced to adipocytes and ADPN expression was knocked down. CSNO was synthesized and patch was constructed. MI model was constructed and patch was placed on the infarcted area. ADPN knockdown adipocytes or control was incubated with CSNO patch, and CCR2 antagonist was also used to investigate the ADPN effects on myocardial injury after infarction. On day 7 after operation, cardiac functions of the mice using CSNO with adipocytes or ADPN knockdown adipocytes improved more than in mice only using CSNO for treatment. Lymphangiogenesis increased much more in the MI mice using CSNO with adipocytes. After treating with CCR2 antagonist, Connexin43+ CD206+ cells and ZO-1+ CD206+ cells increased, suggesting that CCR2 antagonist promoted M2 polarization after MI. Besides, CCR2 antagonist promoted ADPN expression in adipocytes and cardiomyocytes. ELISA was also used and CKMB expression was much lower than other groups at 3 days after operation. On day 7 after operation, the VEGF and TGFβ expressions were high in the adipocytes CSNO group, illustrating that higher ADPN led to better treatment. In all, CCR2 antagonist enhanced the ADPN effects on macrophage M2 polarization and cardiac functions. The combination used in border zone and infarcted areas may help improve patients' prognosis in surgery, such as CABG.
Insights
This study shows that a nitric oxide hydrogel combined with adipocytes improves cardiac function after heart attack. A CCR2 antagonist further enhanced these benefits by promoting beneficial macrophage changes.
Area of Science:
- Biomedical Engineering
- Regenerative Medicine
- Cardiovascular Research
Background:
- Myocardial infarction (MI) significantly impairs cardiac function.
- Limited evidence exists on nitric oxide (NO) hydrogels with adipocytes in vivo.
- Adiponectin (ADPN) and macrophage polarization are key factors in cardiac repair.
Purpose of the Study:
- To investigate the combined effects of adiponectin (ADPN) and a CCR2 antagonist on cardiac function and macrophage phenotypes post-MI.
- To evaluate a chitosan-caged nitric oxide donor (CSNO) patch with adipocytes for treating myocardial infarction.
- To explore ADPN's role in myocardial injury using ADPN-knockdown adipocytes and a CCR2 antagonist.
Main Methods:
- Constructed a myocardial infarction (MI) mouse model and applied a CSNO patch with either control or ADPN-knockdown adipocytes.
- Utilized a CCR2 antagonist to assess its impact on ADPN-mediated effects and macrophage polarization.
- Analyzed cardiac function, lymphangiogenesis, macrophage phenotypes (M2 polarization), and expression of key proteins (Connexin43, ZO-1, CKMB, VEGF, TGFβ).
Main Results:
- CSNO patches with adipocytes significantly improved cardiac function and increased lymphangiogenesis post-MI compared to CSNO alone.
- CCR2 antagonist treatment promoted M2 macrophage polarization (Connexin43+ CD206+, ZO-1+ CD206+ cells) and increased ADPN expression.
- Reduced CKMB levels and elevated VEGF and TGFβ expression were observed, indicating improved cardiac repair and ADPN's beneficial role.
Conclusions:
- The combination of CSNO hydrogel with adipocytes, particularly when enhanced by a CCR2 antagonist, improves cardiac function and promotes beneficial macrophage M2 polarization after MI.
- This therapeutic strategy holds promise for improving patient outcomes in cardiac surgeries like coronary artery bypass grafting (CABG).
- Further research into this combined approach could lead to novel treatments for myocardial infarction and related cardiovascular conditions.
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