Honokiol attenuates angiotensinⅡ-induced hypertensin by inhibiting HDAC6-mediated cystathionine γ-lyase degradation
Honokiol은 HDAC6 에 의한 cystathionine γ-lyase의 분해를 억제하여 angiotensin Ⅱ 유도 고혈압 진행을 완화한다
- 주제(키워드) cystathionine γ-lyase , histone deacetylase 6 , angiotensin II , honokiol , hypertension , hydrogen sulfide , acetylation
- 발행기관 아주대학교
- 지도교수 이숙영
- 발행년도 2021
- 학위수여년월 2021. 2
- 학위명 박사
- 학과 및 전공 일반대학원 의학과
- 실제URI http://www.dcollection.net/handler/ajou/000000030691
- 본문언어 영어
- 저작권 아주대학교 논문은 저작권에 의해 보호받습니다.
초록/요약
Hypertension and endothelial dysfunction are associated with various cardiovascular diseases. Cystathionine γ-lyase (CSE) is an enzyme that produces hydrogen sulfide (H2S). Endothelial H2S production promotes vascular relaxation, supporting to the alleviation of hypertension. Honokiol (HNK) is a natural compound in the Magnolia plant, has been shown to retain multifunctional attributes such as anti-oxidant and anti-inflammatory activity. However, a potential role of HNK in mediating CSE and hypertension remains mostly unknown. Here, We directed to indicate that HNK cotreatment attenuated the hypertension, vasoconstriction, and H2S reduction caused by angiotensin II (AngII), a well-induced inducer of hypertension. Recent studies the part of histone deacetylase 6 (HDAC6) in hypertension has been recommend, but the underlying mechanisms are poorly understood. We found that tubastatin A the HDAC6 inhibitor attenuates angiotensin II induced hypertension by preventing CSE protein degradation. Our results indicate that HNK could improve CSE acetylation levels by inhibiting HDAC6 catalytic activity, By blocking the AngII-induced degradative ubiquitination of CSE. CSE acetylation and ubiquitination happened mainly on the lysine 73 (K73) residue. Conversely, its mutant (K73R) was against to both acetylation and ubiquitination, expressing higher protein stability than that of wild-type CSE. Overall, this study recommend that HNK treatment protects CSE against HDAC6-mediated degradation and may comprise an alternative for preventing endothelial dysfunction and hypertension.
more목차
I. INTRODUCTION 1
II. MATERIALS AND METHODS 5
1. Chemicals 5
2. AngII-infused hypertensive mice and HNK injection 5
3. Blood pressure measurement 6
4. Force tension myography 6
5. Cell cultures and treatments 7
6. H2S measurement 8
7. Antibodies and plasmids 9
8. Transfection and gene knockdown 9
9. Western blotting and immunoprecipitation (IP) 10
10. HNK–HDAC6 binding 10
11. HDAC6 activity assay 11
12. Statistical analysis 11
III. RESULTS 13
1. HNK attenuates AngII-induced hypertension and vascular endothelial dysfunction 13
2. HNK recovers H2S levels decreased by AngII 18
3. HNK increases CSE protein levels by enhancing its stability against proteasomal degradation 22
4. HNK-mediated HDAC6 inhibition induces CSE acetylation, which contributes to CSE Uregulation 29
5. CSE acetylation at K73 prevents its degradative ubiquitination 41
IV. DISCUSSION 49
V. CONCLUSION 54
REFERENCES 55
국문요약 65
