Protein Kinase A-regulated Assembly of a MEF2·HDAC4 Repressor Complex Controls c-Jun Expression in Vascular Smooth Muscle Cells

Gordon, Joseph W.; Pagiatakis, Christina; Jahan, Sultana; Du, Min; Andreucci, John J.; Zhao, Jiahui; Hou, Guangpei; Perry, Robert L.; Dan, Qinghong; Courtman, David W.; Bendeck, Michelle P.; McDermott, John C.

doi:10.1074/jbc.m109.000539

Cited by 62 publications

(73 citation statements)

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“…2B). We have previously demonstrated that c-Jun expression in VSMCs is regulated by a MEF2-HDAC4 repressor complex (6). Consistent with our previous results, the c-jun promoter was repressed by ectopic expression of HDAC4; however, we now demonstrate that this repression can be counteracted by co-expression of an activated CaMKII␦.…”

Section: Depolarization Enhances Mef2-dependent Gene Expression Throusupporting

confidence: 78%

“…Plasmids-MEF2, PP1␣, p38 MAPK (p38 MAPK), MKK6EE, and luciferase constructs were described previously (6,13). The RhoA L63 and C3 transferase expression vectors were kindly provided by A.…”

Section: Methodsmentioning

confidence: 99%

“…Quantitative RT-PCR-Total RNA was isolated from primary VSMCs using a Cell-to-cDNA kit (Ambion), and quantitative PCR was performed using SYBR green (Applied Biosystems), and analyzed using the ⌬⌬CT method, as described previously (6).…”

Section: Methodsmentioning

confidence: 99%

“…Like SRF, MEF2 regulates the expression of immediate early genes, such as c-jun, and recent studies have suggested that c-jun expression in VSMCs is CaMK-dependent (6). However, MEF2C has also been shown to be genetically upstream of myocardin and of critical importance to VSMC differentiation (5,10).…”

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confidence: 99%

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A Novel RhoA/ROCK-CPI-17-MEF2C Signaling Pathway Regulates Vascular Smooth Muscle Cell Gene Expression

Pagiatakis

Gordon

Ehyai

et al. 2012

Journal of Biological Chemistry

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Background: MEF2C is essential for vascular smooth muscle development, yet the signaling pathways that regulate its function in this cell type remain largely unknown. Results: We identify a novel regulator of MEF2C in vascular smooth muscle, called CPI-17. Conclusion: Our data identify a genetic pathway involving CPI-17, MEF2C, and myocardin. Significance: These findings have important ramifications during vascular development and for stem cell programming.

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Section: Depolarization Enhances Mef2-dependent Gene Expression Throusupporting

confidence: 78%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

mentioning

confidence: 99%

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A Novel RhoA/ROCK-CPI-17-MEF2C Signaling Pathway Regulates Vascular Smooth Muscle Cell Gene Expression

Pagiatakis

Gordon

Ehyai

et al. 2012

Journal of Biological Chemistry

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“…HDAC4 is expressed in the heart, stem cells, the endothelium, and vascular smooth muscle cells (1,4,12,19,21). Cardioprotective effects of HDAC inhibition against injury have been well identified (45,47,48).…”

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confidence: 99%

Specific inhibition of HDAC4 in cardiac progenitor cells enhances myocardial repairs

Zhang

DeNicola

Qin

et al. 2014

American Journal of Physiology-Cell Physiology

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We have recently shown that in vivo inhibition of histone deacetylase (HDAC) stimulates endogenous myocardial regeneration in infarcted hearts (Zhang L et al. J Pharmacol Exp Ther 341: 285-293, 2012). Furthermore, our observation demonstrates that HDAC inhibition promotes cardiogenesis, which is associated with HDAC4 reduction. However, it remains unknown as to whether specific inhibition of HDAC4 modulates cardiac stem cells (CSCs) to facilitate myocardial repair and to preserve cardiac performance. c-kit ϩ CSCs were isolated from adult mouse hearts and were transfected with HDAC4 siRNA to knockdown HDAC4 of c-kit ϩ CSCs. The transfection of HDAC4 siRNA caused a marked reduction of HDAC4 mRNA and proteins in c-kit ϩ CSCs. Mouse myocardial infarction (MI) was created to assess the effect of HDAC4 inhibition in c-kit ϩ CSCs on myocardial regeneration in vivo when cells were introduced into MI hearts. Transplantation of HDAC4 siRNA-treated c-kit ϩ CSCs into MI hearts improved ventricular function, attenuated ventricular remodeling, and promoted CSC-derived regeneration and neovascularization. Furthermore, Ki67 and BrdU positively proliferative myocytes increased in MI hearts receiving HDAC4 siRNA-treated c-kit ϩ CSCs compared with MI hearts engrafted with control siRNA-treated c-kit ϩ CSCs. In addition, compared with MI hearts engrafted with control adenoviral GFPinfected c-kit ϩ CSCs, MI hearts receiving adenoviral HDAC4-infected c-kit ϩ CSCs exhibited attenuated cardiac functional recovery, CSC-derived regeneration, and neovascularization, which was accompanied with adverse ventricular remodeling and decrease in Ki67 and BrdU positively proliferative myocytes. HDAC4 inhibition facilitated c-kit ϩ CSCs into the differentiation into cardiac lineage commitments in vitro, while HDAC4 overexpression attenuated c-kit ϩ CSC-derived cardiogenesis. Our results indicate that HDAC4 inhibition promotes CSC-derived cardiac regeneration and improves the restoration of cardiac function.heart; HDAC4; regeneration; myocardial infarction; stem cells IT HAS NOW BEEN RECOGNIZED that adult hearts harbor distinct populations of cardiac progenitors (2,25,26,34), which have the potential to differentiate into cardiomyocytes, endothelia, and vascular smooth muscle cells. Furthermore, several studies have shown that these cardiac progenitor cells are capable of differentiating into cardiac tissue and improving cardiac function after a myocardial injury. Exponential advances in stem cell and regenerative biology are beginning to foster a transition toward therapeutic goals for cardiac regenerative medicine (8,14,15,33). However, poor cell viability, proliferation, and inefficient differentiation following transplantation have limited the reparative capacity of these cells in vivo (26,29,39). Thus molecular intervention strategies to enhance cardiac stem cell (CSC) proliferation and survival hold dramatic consequences for enhancing myogenesis and will empower therapeutically relevant implementation of myocardial regeneration. It was repor...

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Calcium‐regulated transcriptional pathways in the normal and pathologic heart

2011

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SummaryThe cytosolic calcium concentration ([Ca 21 ] c ) is key for the regulation of many cellular processes, such cell signaling and proliferation, metabolism, and muscle contraction. In cardiomyocytes, Ca 21 is an important regulator in many cellular functions such electrophysiological processes, excitation-contraction coupling, regulation of contractile proteins activity, energy metabolism, cell death, and transcriptional regulation by the activation of Ca 21 -dependent transcriptional pathways.

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Protein Kinase A-regulated Assembly of a MEF2·HDAC4 Repressor Complex Controls c-Jun Expression in Vascular Smooth Muscle Cells

Cited by 62 publications

References 62 publications

A Novel RhoA/ROCK-CPI-17-MEF2C Signaling Pathway Regulates Vascular Smooth Muscle Cell Gene Expression

A Novel RhoA/ROCK-CPI-17-MEF2C Signaling Pathway Regulates Vascular Smooth Muscle Cell Gene Expression

Specific inhibition of HDAC4 in cardiac progenitor cells enhances myocardial repairs

Calcium‐regulated transcriptional pathways in the normal and pathologic heart

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