Kee Hae Jin, Ryu Yuhee, Seok Young Mi, Choi Sin Young, Sun Simei, Kim Gwi Ran, Jeong Myung Ho
Heart Research Center of Chonnam National, Jebong-ro, Dong-gu, Gwangju, 61469 Republic of Korea.
2Hypertension Heart Failure Research Center, Chonnam National University Hospital, Gwangju, 61469 Republic of Korea.
Clin Hypertens. 2019 Jun 15;25:13. doi: 10.1186/s40885-019-0118-8. eCollection 2019.
The dysregulation of histone deacetylase (HDAC) protein expression or its enzyme activity is implicated in a variety of diseases. Cardiac HDAC6 and HDAC8 enzyme activity induced by deoxycorticosterone acetate (DOCA) hypertension was attenuated by sodium valproate, a pan-HDAC inhibitor. However, the HDAC6-selective inhibitor, tubastatin A, did not attenuate angiotensin II-induced hypertension. The purpose of this study was to investigate whether PCI34051, an HDAC8-selective inhibitor, can modulate angiotensin II-induced hypertension and its regulatory mechanism.
An angiotensin II-regulated mouse model was used in this study. Animals received vehicle or PCI34051 (3 mg·kg - ·day- ) via intraperitoneal injection. Systolic blood pressure was measured by the tail-cuff method. Blood vessel thickness was measured following hematoxylin and eosin staining, VCAM-1 immunohistochemistry was performed in the aortas, and mRNA expression of renin-angiotensin system components, inflammation markers, and NADPH oxidase (Nox) was determined by RT-PCR. The effect of PCI34051 on vasorelaxation was studied in rat aortic rings, and its effect on nitric oxide (NO) production was determined using DAF-FM DA, a fluorescent dye, in human umbilical vascular endothelial cells (HUVECs).
PCI34051 administration reduced systolic blood pressure via downregulation of angiotensin II receptor type 1 (AT1) mRNA expression. PCI34051 treatment attenuated vascular hypertrophy by decreasing E2F3 and GATA6 mRNA expression. Vascular relaxation after PCI34051 treatment was more dependent on vascular endothelial cells and it was blocked by an NO synthase (NOS) inhibitor. In addition, NO production increased in HUVECs after PCI34051 treatment; this was decreased by the NOS inhibitor. The expression of inflammatory molecules and adhesion molecules VCAM-1 and ICAM-1 decreased in the aortas of angiotensin II-infused mice after PCI34051 administration. However, PCI34051 did not affect Nox or its regulatory subunits.
PCI34051 lowered high blood pressure through modulation of arterial remodeling, vasoconstriction, and inflammation in an angiotensin II-induced hypertension model. We suggest that HDAC8 could be a potential therapeutic target for hypertension.
组蛋白脱乙酰酶（HDAC）蛋白表达失调或其酶活性异常与多种疾病相关。脱氧皮质酮醋酸盐（DOCA）诱导的高血压所引起的心脏HDAC6和HDAC8酶活性可被泛HDAC抑制剂丙戊酸钠所减弱。然而，HDAC6选择性抑制剂tubastatin A并未减弱血管紧张素II诱导的高血压。本研究旨在探讨HDAC8选择性抑制剂PCI34051是否能够调节血管紧张素II诱导的高血压及其调控机制。
本研究采用血管紧张素II调节的小鼠模型。动物通过腹腔注射给予溶剂或PCI34051（3mg·kg -1·天-1）。采用尾套法测量收缩压。苏木精-伊红染色后测量血管厚度，对主动脉进行VCAM-1免疫组织化学检测，并通过RT-PCR测定肾素-血管紧张素系统成分、炎症标志物和NADPH氧化酶（Nox）的mRNA表达。在大鼠主动脉环中研究PCI34051对血管舒张的影响，并在人脐静脉血管内皮细胞（HUVECs）中使用荧光染料DAF-FM DA测定其对一氧化氮（NO）生成的影响。
给予PCI34051可通过下调血管紧张素II 1型受体（AT1）mRNA表达降低收缩压。PCI34051治疗通过降低E2F3和GATA6 mRNA表达减轻血管肥厚。PCI34051治疗后的血管舒张更依赖于血管内皮细胞，且被一氧化氮合酶（NOS）抑制剂所阻断。此外，PCI34051治疗后HUVECs中NO生成增加；NOS抑制剂可使其减少。给予PCI34051后，血管紧张素II灌注小鼠主动脉中炎症分子及黏附分子VCAM-1和ICAM-1的表达降低。然而，PCI34051对Nox或其调节亚基无影响。
在血管紧张素II诱导的高血压模型中，PCI34051通过调节动脉重塑、血管收缩和炎症降低高血压。我们认为HDAC8可能是高血压的一个潜在治疗靶点。
