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Honokiol attenuates angiotensinⅡ-induced hypertensin by inhibiting HDAC6-mediated cystathionine γ-lyase degradation

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dc.contributor.advisor이, 숙영-
dc.contributor.authorCHI, ZHEXI-
dc.date.accessioned2021-11-10T05:52:05Z-
dc.date.available2021-11-10T05:52:05Z-
dc.date.issued2021-
dc.identifier.urihttp://repository.ajou.ac.kr/handle/201003/19795-
dc.description.abstractHypertension 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.-
dc.description.abstract고혈압 및 혈관 내피 기능 장애는 다양한 심혈관 질환과 관련이 있다. Cystathionine γ-lyase (CSE)는 황화수소 (H2S)를 생성하는 효소이다. 혈관 내에서 생성되는 황화 수소는 혈관의 이완을 촉진하고 고혈압의 완화에 기여하고 있는 것으로 알려져 있다. Honokiol (HNK)는 목련나무에서 추출되는 천연 화합물이고 항산화 작용과 항염증 작용 등 다기능 특성을 유지하고 있다. 그러나 CSE 와 고혈압의 조절에 있어서 HNK 의 잠재적인 역할은 아직 알려지지 않았다. 여기서 우리는 Honokiol 치료가 angiotensin II (AngII)에 의한 고혈압 유발 혈관수축, H2S 의 감소를 완화하는 것을 확인 하려고 한다. 최근 연구에서는 고혈압의 histone deacetylase 6 (HDAC6)의 역할이 시사되고 있지만 근본적인 메커니즘은 잘 알려져 있지 않다. Histone deacetylase 6 (HDAC6) 억제제인 tubastatin A 가 angiotensin II 유도 고혈압에서 CSE 단백질의 분해를 저해하여 고혈압을 완화시키는 것을 발견하였다. 우리의 결과는 HNK 이 AngII 에 의한 CSE 의 분해 ubiquitination 을 차단함으로써 HDAC6 촉매 활성을 저해 하는 것으로 CSE acetylation 수준을 증가 할 수 있음을 보여주었다. CSE 의 acetylation 및 ubiquitination 는 주로 lysine 73 (K73) 위치에서 발생한다. 반대로, 돌연변이 (K73R)은 acetylation 및 ubiquitination 에 모두 내성이 CSE 보다 높은 단백질 안정성을 보여 주었다. 전반적으로, 이번 연구는 HNK 치료가 HDAC6 을 통해 분해로부터 CSE 를 보호 하고 내피 기능 장애와 고혈압을 예방하기 위한 대안이 될 가능성이 있음을 시사하고 있다.-
dc.description.tableofcontentsI. 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
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dc.language.isoen-
dc.titleHonokiol attenuates angiotensinⅡ-induced hypertensin by inhibiting HDAC6-mediated cystathionine γ-lyase degradation-
dc.title.alternativeHonokiol은 HDAC6 에 의한 cystathionine γ-lyase의 분해를 억제하여 angiotensin Ⅱ 유도 고혈압 진행을 완화한다-
dc.typeThesis-
dc.identifier.urlhttp://dcoll.ajou.ac.kr:9080/dcollection/jsp/common/DcLoOrgPer.jsp?sItemId=000000030691-
dc.subject.keywordcystathionine γ-lyase-
dc.subject.keywordhistone deacetylase 6-
dc.subject.keywordangiotensin II-
dc.subject.keywordhonokiol-
dc.subject.keywordhypertension-
dc.subject.keywordhydrogen sulfide-
dc.subject.keywordacetylation-
dc.subject.keyword황화수소-
dc.subject.keyword고혈압-
dc.description.degreeDoctor-
dc.contributor.department대학원 의학과-
dc.contributor.affiliatedAuthorCHI, ZHEXI-
dc.date.awarded2021-
dc.type.localTheses-
dc.citation.date2021-
dc.embargo.liftdate9999-12-31-
dc.embargo.terms9999-12-31-
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