아디포카인 CTRP9의 항동맥경화 및 심근보호 효과: HDAC7-MEF2 매개 혈관신생 기전과 치료적 의의 = Atheroprotective and Cardioprotective Functions of CTRP9 : HDAC7-MEF2-Mediated Vascular Angiogenesis and Therapeutic Implications

다국어 초록 (Multilingual Abstract)

C1q/tumor necrosis factor-related protein 9 (CTRP9) is an adipokine with significant potential as a therapeutic target for cardiovascular diseases. However, its precise role in the pathogenesis of cardiovascular disease and the underlying molecular mechanisms remain incompletely understood. In this study, we discovered that CTRP9 induces phosphorylation of histone deacetylase 7 (HDAC7) and p38 mitogen-activated protein kinase (MAPK) through tight regulation of adenosine monophosphate-activated protein kinase (AMPK) in vascular endothelial cells. This signaling cascade promotes angiogenesis by enhancing the transcriptional activity of myocyte enhancer factor 2 (MEF2). Notably, the expression of CTRP9 and the atheroprotective transcription factor MEF2 was significantly reduced in atherosclerotic plaques from patients and in the ventricles of mice following myocardial infarction (MI), suggesting a critical role in cardiovascular pathology. Functional studies revealed that CTRP9 treatment effectively inhibited atherosclerotic plaque formation in ApoE knockout and CTRP9 knockout miceFurthermore, CTRP9 administration significantly attenuated ischemic injury in a mouse model of MI. Translating these findings to clinical relevance, serum CTRP9 levels were markedly reduced in MI patients compared with healthy controls, and Area Under the Receiver Operating Characteristic curve (AUROC) analysis revealed that CTRP9 exhibits clinically significant specificity and sensitivity as a diagnostic biomarker. In summary, CTRP9 elicits a vasoprotective response via the AMPK/HDAC7/p38 MAPK pathway in vascular endothelial cells, while its deficiency accelerates the progression of atherosclerosis and MI. Thus, CTRP9 represents a promising therapeutic target and diagnostic biomarker for cardiovascular diseases.

목차 (Table of Contents)

• Abstract i
• List of figures iv
• Introduction 1
• 1. Statement of problem 1
• 2. Propose of study 4
• 3. Theoretical background 6
• Materials and methods 20
• Results 32
• 1. CTRP9 regulated phosphorylation of AMPK and HDAC7 in HUVECs 32
• 2. CTRP9-induced phosphorylation of HDAC7 promoted MEF2 activity via nuclear export 35
• 3. CTRP9 induced p38 MAPK phosphorylation, thereby regulating VEGF secretion and MEF2 activity 38
• 4. CTRP9-induced AMPK activation consequently regulated HDAC7 and p38 MAPK phosphorylation 41
• 5. CTRP9 induced an early angiogenic response in HUVECs 43
• 6. Genetic inhibition of AMPK, HDAC7, and p38 MAPK impaired CTRP9-induced angiogenesis 46
• 7. CTRP9 deficiency impaired angiogenesis in vivo 49
• 8. Comprehensive transcriptomic analysis demonstrated CTRP9-mediated regulation of MEF 2 and atheroprotective pathways in vascular endothelium 52
• 9. CTRP9 Deficiency Drove Endothelial Dysfunction by Activating Pro-Atherogenic Stress Pathways 55
• 10. KEGG and GO analyses established molecular pathways underlying CTRP9's vasoprotective roles 58
• 11. Systemic characterization of CTRP9 KO mice revealed proinflammatory immune profiles 61
• 12. CTRP9 deficiency selectively impaired thermogenic gene expression programs in adipose tissue without altering gross metabolic phenotype 64
• 13. CTRP9 deficiency exacerbated atherosclerosis 66
• 14. Recombinant CTRP9 exhibited potent atheroprotection and effectively reduced plaque burden in both the aorta and carotid artery independent of endogenous CTRP9 status 69
• 15. CTRP9 decreased during MI, and recombinant CTRP9 conferred cardioprotection 72
• 16. Cardiac MRI revealed CTRP9 administration preserved left ventricular contractility and prevented adverse remodeling following myocardial infarction 76
• 17. CTRP9 deficiency correlated with an increased burden of metabolic risk factors in CAD-prone subjects 78
• 18. Serum CTRP9 depletion was a consistent pathological feature of myocardial infarction independent of coronary vessel damage extent 80
• 19. CTRP9 depletion in MI patients was modulated by vascular comorbidities and demonstrated sex-dependent differences 83
• 20. Circulating CTRP9 levels inversely correlated with myocardial infarction severity and demonstrated robust diagnostic performance 87
• Discussion 90
• Conclusion 101
• References 102
• 국문요약 109