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Endothelial Arg2 regulates HIMM-induced mitochondrial hyperfission via affecting arginine metabolism
Feng Guo1, Xinyi Chen2, Meijiang Chen2
1Institute of Traditional Chinese Medicine and Brain Science, Shandong University of Traditional Chinese Medicine, Jinan, China; Institute of Acupuncture and Moxibustion, Shandong University of Traditional Chinese Medicine, Jinan, China.
Background:
Pathological features of cardiovascular complications remain persistent in diabetic patients, even under strict blood glucose control. Hyperglycemia-induced metabolic memory (HIMM) in endothelial cells (ECs) is a significant contributor to this phenomenon, particularly through its effects on mitochondrial function. Arginase2 (Arg2), a mitochondrial enzyme, plays a crucial role in regulating mitochondrial and vascular homeostasis in various vascular diseases, but the role of endothelial Arg2 in HIMM remains unclear.
Methods:
We established both in vivo (HIMM-mouse model) and in vitro (HIMM-EC model) systems to assess the activation status of arginase 2 (Arg2), alterations in arginine metabolism, and mitochondrial function. Endothelial-specific Arg2-overexpressing and knockout mice were generated to evaluate the critical role of Arg2 in cardiovascular function and HIMM-induced protection via ultrasound imaging system, laser speckle flowmetry, myograph, and immunofluorescence staining. Arg2-knockout/overexpression cell lines were established and mitochondrial function and its regulatory mechanisms in response to damage was assessed using MitoSOX, MitoTracker, oxygen consumption rate (OCR), and Western blot.
Results:
We initially observed that HIMM triggered significant Arg2 activation, arginine metabolism dysregulation, mitochondrial dysfunction, and vascular impairment in both in vivo and in vitro models. Endothelial-specific Arg2 overexpression successfully recapitulated these pathological phenotypes, leading to endothelial damage and vascular dysfunction. Further we confirmed that endothelial Arg2 knockout effectively protected against HIMM-induced endothelial damage, mitochondrial hyper-fragmentation, and cardiac dysfunction. These improvements were mediated by correcting aberrant Arg2 expression, which restored arginine levels, activated the NO-cGMP-PKG signaling pathway, and ultimately suppressed excessive mitochondrial fission, leading to improved cardiovascular function.
Conclusion:
Our findings highlight the critical role of endothelial Arg2 in maintaining vascular homeostasis via arginine metabolism and mitochondrial fission. This identifies Arg2 as a promising therapeutic target for HIMM-related vascular diseases.
Insights
Hyperglycemia-induced metabolic memory (HIMM) activates arginase 2 (Arg2) in endothelial cells, causing vascular damage. Blocking Arg2 protects against HIMM-related cardiovascular complications by restoring arginine metabolism and mitochondrial function.
Area of Science:
- Cardiovascular Biology
- Mitochondrial Biology
- Endothelial Cell Biology
Background:
- Cardiovascular complications persist in diabetic patients despite glucose control.
- Hyperglycemia-induced metabolic memory (HIMM) in endothelial cells (ECs) contributes to these complications, impacting mitochondrial function.
- The role of endothelial arginase 2 (Arg2) in HIMM is not well understood.
Purpose of the Study:
- To investigate the role of endothelial Arg2 in HIMM-induced cardiovascular dysfunction.
- To elucidate the mechanisms by which Arg2 affects arginine metabolism and mitochondrial function in HIMM.
- To assess Arg2 as a potential therapeutic target for HIMM-related vascular diseases.
Main Methods:
- Established in vivo (HIMM-mouse model) and in vitro (HIMM-EC model) systems.
- Utilized endothelial-specific Arg2-overexpressing and knockout mice and cell lines.
- Assessed Arg2 activation, arginine metabolism, mitochondrial function (MitoSOX, MitoTracker, OCR), and vascular function (ultrasound, laser speckle, myograph).
Main Results:
- HIMM induced Arg2 activation, arginine dysregulation, mitochondrial dysfunction, and vascular impairment.
- Endothelial Arg2 overexpression mimicked HIMM pathology, causing endothelial and vascular damage.
- Endothelial Arg2 knockout protected against HIMM-induced damage, restoring arginine levels, NO-cGMP-PKG signaling, and suppressing mitochondrial fission, improving cardiovascular function.
Conclusions:
- Endothelial Arg2 plays a critical role in HIMM-related vascular dysfunction.
- Arg2 regulates vascular homeostasis through arginine metabolism and mitochondrial fission.
- Arg2 is a potential therapeutic target for hyperglycemia-induced metabolic memory vascular diseases.
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