Endothelial MICU1 alleviates diabetic cardiomyopathy by attenuating nitrative stress-mediated cardiac microvascular injury
- Cardiovasc Diabetol. 2023 Aug 17;22(1):216. doi: 10.1186/s12933-023-01941-1.
- 1. Department of Cardiology, Xijing Hospital, The Fourth Military Medical University, Xi'an, China.
- 2. State Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration, National Clinical Research Center for Oral Diseases, Shaanxi Clinical Research Center for Oral Diseases, Department of Medical Rehabilitation, School of Stomatology, The Fourth Military Medical University, Xi'an, China.
- 3. Aerospace Clinical Medical Center, School of Aerospace Medicine, The Fourth Military Medical University, 169 Changle West Road, Xi'an, 710032, Shaanxi, China.
- 4. Department of Physiology and Pathophysiology, State Key Laboratory of Cancer Biology, The Fourth Military Medical University, Xi'an, China.
- 5. Aerospace Clinical Medical Center, School of Aerospace Medicine, The Fourth Military Medical University, 169 Changle West Road, Xi'an, 710032, Shaanxi, China. [email protected].
- 6. Department of Aviation Medicine, Xijing Hospital, The Fourth Military Medical University, Xi'an, China. [email protected].
- 7. Aerospace Clinical Medical Center, School of Aerospace Medicine, The Fourth Military Medical University, 169 Changle West Road, Xi'an, 710032, Shaanxi, China. [email protected].
- 8. Department of Aviation Medicine, Xijing Hospital, The Fourth Military Medical University, Xi'an, China. [email protected].
- 9. Department of Cardiology, Xijing Hospital, The Fourth Military Medical University, Xi'an, China. [email protected].
- 10. Department of Aviation Medicine, Xijing Hospital, The Fourth Military Medical University, Xi'an, China. [email protected].
- # Contributed equally.
Background: Myocardial microvascular injury is the key event in early diabetic Heart Disease. The injury of myocardial microvascular endothelial cells (CMECs) is the main cause and trigger of myocardial microvascular disease. Mitochondrial calcium homeostasis plays an important role in maintaining the normal function, survival and death of endothelial cells. Considering that mitochondrial calcium uptake 1 (MICU1) is a key molecule in mitochondrial calcium regulation, this study aimed to investigate the role of MICU1 in CMECs and explore its underlying mechanisms.
Methods: To examine the role of endothelial MICU1 in diabetic Cardiomyopathy (DCM), we used endothelial-specific MICU1ecKO mice to establish a diabetic mouse model and evaluate the cardiac function. In addition, MICU1 overexpression was conducted by injecting adeno-associated virus 9 carrying MICU1 (AAV9-MICU1). Transcriptome Sequencing technology was used to explore underlying molecular mechanisms.
Results: Here, we found that MICU1 expression is decreased in CMECs of diabetic mice. Moreover, we demonstrated that endothelial cell MICU1 knockout exacerbated the levels of cardiac hypertrophy and interstitial myocardial fibrosis and led to a further reduction in left ventricular function in diabetic mice. Notably, we found that AAV9-MICU1 specifically upregulated the expression of MICU1 in CMECs of diabetic mice, which inhibited nitrification stress, inflammatory reaction, and Apoptosis of the CMECs, ameliorated myocardial hypertrophy and fibrosis, and promoted cardiac function. Further mechanistic analysis suggested that MICU1 deficiency result in excessive mitochondrial calcium uptake and homeostasis imbalance which caused nitrification stress-induced endothelial damage and inflammation that disrupted myocardial microvascular endothelial barrier function and ultimately promoted DCM progression.
Conclusions: Our findings demonstrate that MICU1 expression was downregulated in the CMECs of diabetic mice. Overexpression of endothelial MICU1 reduced nitrification stress induced Apoptosis and inflammation by inhibiting mitochondrial calcium uptake, which improved myocardial microvascular function and inhibited DCM progression. Our findings suggest that endothelial MICU1 is a molecular intervention target for the potential treatment of DCM.