Histone deacetylase and GATA-binding factor 6 regulate arterial remodeling in angiotensin II-induced hypertension

Kim, Gwi Ran; Cho, Soo-Na; Kim, Hyung-Seok; Yu, Seon Young; Choi, Sin Young; Ryu, Yuhee; Lin, Ming Quan; Jin, Li; Kee, Hae Jin; Jeong, Myung Ho

doi:10.1097/hjh.0000000000001081

Cited by 30 publications

(33 citation statements)

References 37 publications

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“…Arterial remodelling is associated with hypertension, and it was reported that angiotensin II stimuli induces VSMC hypertrophy and hyperplasia . In the present study, we showed that LMK235 reduces aortic wall thickness induced by angiotensin II infusion or SHRs.…”

Section: Discussionsupporting

confidence: 67%

“…Previously, we demonstrated that MC1568 attenuates vascular hypertrophy and hyperplasia both in angiotensin II-induced hypertensive mice and VSMCs. 11 To determine whether LMK235 can affect arterial wall thickness, we measured wall thickness after H&E staining. As shown in Figure 4A,B, LMK235 treatment for 1 week with 3 mg/kg/ day completely inhibited the increased aortic wall thickness in angiotensin II-infusion mice.…”

Section: Lmk235 Decreases the Increased Aortic Wall Thickness In Hymentioning

confidence: 99%

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

Choi

Kee

Sun

et al. 2019

J Cellular Molecular Medi

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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.

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Section: Discussionsupporting

confidence: 67%

Section: Lmk235 Decreases the Increased Aortic Wall Thickness In Hymentioning

confidence: 99%

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

Choi

Kee

Sun

et al. 2019

J Cellular Molecular Medi

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“…A scaffold protein GRK2 interacting protein 1 mediates ANG II-induced HDAC phosphorylation in VSMC (795). siRNA studies further confirm the roles of HDAC4 and GATA6 in VSMC hypertrophy induced by ANG II (492). Global deletion of HDAC6 in class IIb HDAC6-deficient mice protected mice from ANG II-induced cardiac systolic dysfunction and skeletal muscle wasting.…”

Section: Acetylation/deacetylationmentioning

confidence: 73%

Angiotensin II Signal Transduction: An Update on Mechanisms of Physiology and Pathophysiology

Forrester

Booz

Sigmund

et al. 2018

Physiological Reviews

787

780

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The renin-angiotensin-aldosterone system plays crucial roles in cardiovascular physiology and pathophysiology. However, many of the signaling mechanisms have been unclear. The angiotensin II (ANG II) type 1 receptor (ATR) is believed to mediate most functions of ANG II in the system. ATR utilizes various signal transduction cascades causing hypertension, cardiovascular remodeling, and end organ damage. Moreover, functional cross-talk between ATR signaling pathways and other signaling pathways have been recognized. Accumulating evidence reveals the complexity of ANG II signal transduction in pathophysiology of the vasculature, heart, kidney, and brain, as well as several pathophysiological features, including inflammation, metabolic dysfunction, and aging. In this review, we provide a comprehensive update of the ANG II receptor signaling events and their functional significances for potential translation into therapeutic strategies. ATR remains central to the system in mediating physiological and pathophysiological functions of ANG II, and participation of specific signaling pathways becomes much clearer. There are still certain limitations and many controversies, and several noteworthy new concepts require further support. However, it is expected that rigorous translational research of the ANG II signaling pathways including those in large animals and humans will contribute to establishing effective new therapies against various diseases.

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“…They reported that MC1568 (a class IIa HDAC inhibitor) prevented the increase in activation of HDAC4 in neointimal lesions through p38 mitogen-activated protein kinase/heat shock protein 27 signals. In our most recently published paper, we demonstrated that HDAC4 and GATA-binding factor 6 (GATA6) expression levels were increased in the kidney and thoracic aorta in Ang II-induced hypertensive mice 19). We also showed that MC1568 treatment lowered increased blood pressure and weakened the association between HDAC4 and calcium/calmodulin-dependent kinase IIα, which is implicated in vascular hypertrophy and hyperplasia.…”

Section: Discussionmentioning

confidence: 89%

Expression of Class I and Class II a/b Histone Deacetylase is Dysregulated in Hypertensive Animal Models

et al. 2017

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Background and ObjectivesDysregulation of histone deacetylase expression and enzymatic activity is associated with a number of diseases. It has been reported that protein levels of histone deacetylase (HDAC)1 and HDAC5 increase during human pulmonary hypertension, and that the enzymatic activity of HDAC6 is induced in a chronic hypertensive animal model. This study investigated the protein expression profiles of class I and II a/b HDACs in three systemic hypertension models.Subjects and MethodsWe used three different hypertensive animal models: (i) Wistar-Kyoto rats (n=8) and spontaneously hypertensive rats (SHR; n=8), (ii) mice infused with saline or angiotensin II to induce hypertension, via osmotic mini-pump for 2 weeks, and (iii) mice that were allowed to drink L-NG-nitro-L-arginine methyl ester (L-NAME) to induce hypertension.ResultsSHR showed high systolic, diastolic, and mean blood pressures. Similar increases in systolic blood pressure were observed in angiotensin II or L-NAME-induced hypertensive mice. In SHR, class IIa HDAC (HDAC4, 5, and 7) and class IIb HDAC (HDAC6 and 10) protein expression were significantly increased. In addition, a HDAC3 protein expression was induced in SHR. However, in L-NAME mice, class IIa HDAC protein levels (HDAC4, 5, 7, and 9) were significantly reduced. HDAC8 protein levels were significantly reduced both in angiotensin II mice and in SHR.ConclusionThese results indicate that dysregulation of class I and class II HDAC protein is closely associated with chronic hypertension.

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Histone deacetylase and GATA-binding factor 6 regulate arterial remodeling in angiotensin II-induced hypertension

Abstract: These results suggest that class II HDAC inhibition attenuates hypertension by negatively regulating VSMC hypertrophy and hyperplasia via the CaMKIIα/protein kinase D1/HDAC4/GATA6 pathway.

Cited by 30 publications

References 37 publications

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

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

Angiotensin II Signal Transduction: An Update on Mechanisms of Physiology and Pathophysiology

Expression of Class I and Class II a/b Histone Deacetylase is Dysregulated in Hypertensive Animal Models

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