Magnesium lithospermate B enhances the potential of human-induced pluripotent stem cell-derived cardiomyocytes for myocardial repair

Chengming Fan; Kele Qin; Chukwuemeka Daniel Iroegbu; Kun Xiang; Yibo Gong; Qing Guan; Wenxiang Wang; Jun Peng; Jianjun Guo; Xun Wu; Jinfu Yang

doi:10.1097/CM9.0000000000002867

Magnesium lithospermate B enhances the potential of human-induced pluripotent stem cell-derived cardiomyocytes for myocardial repair

Chin Med J (Engl). 2024 Jan 15. doi: 10.1097/CM9.0000000000002867. Online ahead of print.

Authors

Chengming Fan^{1

2

3}, Kele Qin¹, Chukwuemeka Daniel Iroegbu¹, Kun Xiang¹, Yibo Gong¹, Qing Guan¹, Wenxiang Wang⁴, Jun Peng², Jianjun Guo³, Xun Wu^{1

4}, Jinfu Yang¹

Affiliations

¹ Department of Cardiovascular Surgery, The Second Xiangya Hospital, Central South University, Changsha, Hunan 410011, China.
² Department of Pharmacology, Xiangya School of Pharmaceutical Sciences, Central South University, Changsha, Hunan 410078, China.
³ Hunan Fangsheng Pharmaceutical Co., Ltd., Changsha, Hunan 410000, China.
⁴ Department of Thoracic Surgery, The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, Hunan 41000, China.

PMID: 38221772
DOI: 10.1097/CM9.0000000000002867

Abstract

Background: We previously reported that activation of the cell cycle in human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) enhances their remuscularization capacity after human cardiac muscle patch transplantation in infarcted mouse hearts. Herein, we sought to identify the effect of magnesium lithospermate B (MLB) on hiPSC-CMs during myocardial repair using a myocardial infarction (MI) mouse model.

Methods: In C57BL/6 mice, MI was surgically induced by ligating the left anterior descending coronary artery. The mice were randomly divided into five groups (n = 10 per group); a MI group (treated with phosphate-buffered saline only), a hiPSC-CMs group, a MLB group, a hiPSC-CMs + MLB group, and a Sham operation group. Cardiac function and MLB therapeutic efficacy were evaluated by echocardiography and histochemical staining 4 weeks after surgery. To identify the associated mechanism, nuclear factor (NF)-κB p65 and intercellular cell adhesion molecule-1 (ICAM1) signals, cell adhesion ability, generation of reactive oxygen species, and rates of apoptosis were detected in human umbilical vein endothelial cells (HUVECs) and hiPSC-CMs.

Results: After 4 weeks of transplantation, the number of cells that engrafted in the hiPSC-CMs + MLB group was about five times higher than those in the hiPSC-CMs group. Additionally, MLB treatment significantly reduced tohoku hospital pediatrics-1 (THP-1) cell adhesion, ICAM1 expression, NF-κB nuclear translocation, reactive oxygen species production, NF-κB p65 phosphorylation, and cell apoptosis in HUVECs cultured under hypoxia. Similarly, treatment with MLB significantly inhibited the apoptosis of hiPSC-CMs via enhancing signal transducer and activator of transcription 3 (STAT3) phosphorylation and B-cell lymphoma-2 (BCL2) expression, promoting STAT3 nuclear translocation, and downregulating BCL2-Associated X, dual specificity phosphatase 2 (DUSP2), and cleaved-caspase-3 expression under hypoxia. Furthermore, MLB significantly suppressed the production of malondialdehyde and lactate dehydrogenase and the reduction in glutathione content induced by hypoxia in both HUVECs and hiPSC-CMs in vitro.

Conclusions: MLB significantly enhanced the potential of hiPSC-CMs in repairing injured myocardium by improving endothelial cell function via the NF-κB/ICAM1 pathway and inhibiting hiPSC-CMs apoptosis via the DUSP2/STAT3 pathway.