Histone deacetylase inhibitor LMK235 attenuates vascular constriction and aortic remodelling in hypertension.

ABSTRACT: 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) ?, which is related to vascular smooth muscle cell proliferation. Inhibition or knockdown of HDAC5 blocked the CaMKII?-induced cell cycle gene expression. Immunoprecipitation demonstrated that class I HDACs were involved in the inhibition of CaMKII ?-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.

SUBMITTER: Choi SY 

PROVIDER: S-EPMC6433685 | biostudies-literature | 2019 Apr

REPOSITORIES: biostudies-literature