Histone deacetylase inhibitor LMK235 attenuates vascular constriction and aortic remodelling in hypertension
| العنوان: | Histone deacetylase inhibitor LMK235 attenuates vascular constriction and aortic remodelling in hypertension |
|---|---|
| المؤلفون: | Seung-Jung Kee, Marc Pflieger, Thomas Kurz, Hae Jin Kee, Gwi Ran Kim, Simei Sun, Matthias U. Kassack, Sin Young Choi, Young Mi Seok, Yuhee Ryu, Myung Ho Jeong |
| المصدر: | Journal of Cellular and Molecular Medicine |
| بيانات النشر: | John Wiley and Sons Inc., 2019. |
| سنة النشر: | 2019 |
| مصطلحات موضوعية: | 0301 basic medicine, Male, Angiotensin receptor, medicine.medical_specialty, Vascular smooth muscle, hypertension, medicine.drug_class, Aortic Diseases, Muscle, Smooth, Vascular, Nitric oxide, Rats, Sprague-Dawley, 03 medical and health sciences, chemistry.chemical_compound, Mice, 0302 clinical medicine, calcium calmodulin‐dependent protein kinase II, Internal medicine, Rats, Inbred SHR, Renin–angiotensin system, medicine, Animals, Antihypertensive Agents, Histone deacetylase 5, vascular hyperplasia, Angiotensin II, Histone deacetylase inhibitor, Cell Biology, Original Articles, HDAC5, HDAC4, Rats, Histone Deacetylase Inhibitors, 030104 developmental biology, Endocrinology, chemistry, Gene Expression Regulation, Vasoconstriction, 030220 oncology & carcinogenesis, Benzamides, Molecular Medicine, Original Article, medicine.symptom |
| الوصف: | Here, we report that LMK235, a class I and histone deacetylase (HDAC6)‐preferential HDAC inhibitor, reduces hypertension via inhibition of vascular contraction and vessel hypertrophy. Angiotensin II‐infusion mice and spontaneously hypertensive rats (SHRs) were used to test the anti‐hypertensive effect of LMK235. Daily injection of LMK235 lowered angiotensin II‐induced systolic blood pressure (BP). A reduction in systolic BP in SHRs was observed on the second day when SHRs were treated with 3 mg/kg LMK235 every 3 days. However, LMK235 treatment did not affect angiotensin‐converting enzyme 1 and angiotensin II receptor mRNA expression in either hypertensive model. LMK235, acting via the nitric oxide pathway, facilitated the relaxing of vascular contractions induced by a thromboxane A2 agonist in the rat aortic and mesenteric artery ring test. In addition, LMK235 increased nitric oxide production in HUVECs and inhibited the increasing of aortic wall thickness in both animal hypertensive models. LMK235 decreased the enhanced cell cycle‐related genes cyclin D1 and E2F3 in angiotensin II‐infusion mice and restored the decreased p21 expression. In addition, LMK235 suppressed calcium calmodulin‐dependent protein kinase II (CaMKII) α, which is related to vascular smooth muscle cell proliferation. Inhibition or knockdown of HDAC5 blocked the CaMKIIα‐induced cell cycle gene expression. Immunoprecipitation demonstrated that class I HDACs were involved in the inhibition of CaMKII α‐induced HDAC4/5 by LMK235. We suggest that LMK235 should be further investigated for its use in the development of new therapeutic options to treat hypertension via reducing vascular hyperplasia or vasoconstriction. |
| اللغة: | English |
| تدمد: | 1582-4934 1582-1838 |
| الوصول الحر: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::864b3a40fdb5d328dc25c76d3bf1cb31Test http://europepmc.org/articles/PMC6433685Test |
| حقوق: | OPEN |
| رقم الانضمام: | edsair.doi.dedup.....864b3a40fdb5d328dc25c76d3bf1cb31 |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 15824934 15821838 |
|---|