Transcription factors Csx/Nkx2.5 and GATA4 distinctly regulate expression of Ca2+ channels in neonatal rat heart

Wang, Yan; Miyamoto, Masaki; Zheng, Mingqi; Uchino, Tetsuya; Mannen, Kazuaki; Takahashi, Akira; Nakaya, Yutaka; Komuro, Issei; Ono, Katsushige

doi:10.1016/j.yjmcc.2007.03.905

Cited by 50 publications

(35 citation statements)

References 26 publications

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“…The cardiac transcription factors Nkx2.5 and GATA4 play important roles in vertebrate cardiac development. Nkx2.5 and GATA4 were initially identified as the genes causing congenital heart disease (Granados-Riveron et al, 2012;Wang et al, 2007). Nkx2.5 and GATA4 expression was dramatically reduced by high-salt exposure (Fig.…”

Section: Discussionmentioning

confidence: 99%

The impact of high salt exposure on cardiovascular development in the early chick embryo

Wang

Zhang

Wei

et al. 2015

Journal of Experimental Biology

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In this study, we show that high-salt exposure dramatically increases chick mortality during embryo development. As embryonic mortality at early stages mainly results from defects in cardiovascular development, we focused on heart formation and angiogenesis. We found that high-salt exposure enhanced the risk of abnormal heart tube looping and blood congestion in the heart chamber. In the presence of high salt, both ventricular cell proliferation and apoptosis increased. The high osmolarity induced by high salt in the ventricular cardiomyocytes resulted in incomplete differentiation, which might be due to reduced expression of Nkx2.5 and GATA4. Blood vessel density and diameter were suppressed by exposure to high salt in both the yolk sac membrane (YSM) and chorioallantoic membrane models. In addition, high-salt-induced suppression of angiogenesis occurred even at the vasculogenesis stage, as blood island formation was also inhibited by high-salt exposure. At the same time, cell proliferation was repressed and cell apoptosis was enhanced by high-salt exposure in YSM tissue. Moreover, the reduction in expression of HIF2 and FGF2 genes might cause high-saltsuppressed angiogenesis. Interestingly, we show that high-salt exposure causes excess generation of reactive oxygen species (ROS) in the heart and YSM tissues, which could be partially rescued through the addition of antioxidants. In total, our study suggests that excess generation of ROS might play an important role in high-saltinduced defects in heart and angiogenesis.

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Section: Discussionmentioning

confidence: 99%

The impact of high salt exposure on cardiovascular development in the early chick embryo

Wang

Zhang

Wei

et al. 2015

Journal of Experimental Biology

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“…Although activation and deactivation of T-type Ca 2ϩ channel gene expression has been observed in many pathological conditions and under various stimuli (4, 26, 35), transcription factors involved in such gene regulation are just beginning to emerge. For instance, repressor element-1 silencing transcription factor, also known as neuron-restrictive silencer factor (15,36), early growth response factor-1 (ERG1) (12), transcription factor GATA4 (28), cardiac homeobox transcription factor Csx/Nkx2.5 (38), and LEF1/␤-catenin complex (39) have been reported to function as a transcriptional regulator of ␣ 1H . However, it is of note that, among these identified transcription factors, ERG1, GATA4, NKX2.5, as well as ␤-catenin signaling have been reported to be regulated by hypoxia (13,25,28,41).…”

Section: Discussionmentioning

confidence: 99%

Transcriptional regulation of α_1H T-type calcium channel under hypoxia

Hassan

Zhou

Liu

et al. 2014

American Journal of Physiology-Cell Physiology

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scriptional regulation of ␣1H T-type calcium channel under hypoxia. Am J Physiol Cell Physiol 307: C648 -C656, 2014. First published August 6, 2014; doi:10.1152/ajpcell.00210.2014.-The low-voltageactivated T-type Ca 2ϩ channels play an important role in mediating the cellular responses to altered oxygen tension. Among three T-type channel isoforms, ␣1G, ␣1H, and ␣1I, only ␣1H was found to be upregulated under hypoxia. However, mechanisms underlying such hypoxia-dependent isoform-specific gene regulation remain incompletely understood. We, therefore, studied the hypoxia-dependent transcriptional regulation of ␣1G and ␣1H gene promoters with the aim to identify the functional hypoxia-response elements (HREs). In rat pulmonary artery smooth muscle cells (PASMCs) and pheochromocytoma (PC12) cells after hypoxia (3% O2) exposure, we observed a prominent increase in ␣ 1H mRNA at 12 h along with a significant rise in ␣ 1H-mediated T-type current at 24 and 48 h. We then cloned two promoter fragments from the 5=-flanking regions of rat ␣ 1G and ␣1H gene, 2,000 and 3,076 bp, respectively, and inserted these fragments into a luciferase reporter vector. Transient transfection of PASMCs and PC12 cells with these recombinant constructs and subsequent luciferase assay revealed a significant increase in luciferase activity from the reporter containing the ␣1H, but not ␣1G, promoter fragment under hypoxia. Using serial deletion and point mutation analysis strategies, we identified a functional HRE at site Ϫ1,173CACGCϪ1,169 within the ␣ 1H promoter region. Furthermore, an electrophoretic mobility shift assay using this site as a DNA probe demonstrated an increased binding activity to nuclear protein extracts from the cells after hypoxia exposure. Taken together, these findings indicate that hypoxia-induced ␣ 1H upregulation involves binding of hypoxia-inducible factor to an HRE within the ␣1H promoter region.T-type calcium channel; gene expression; hypoxia; hypoxia-response element HYPOXIA IS AN ESSENTIAL and critical pathological component of many pulmonary disorders, including acute lung injury, chronic obstructive pulmonary disease, and pulmonary hypertension. One of the most important responses to hypoxia in the pulmonary vasculature is a change in intracellular calcium homeostasis. Smooth muscle cells in pulmonary arteries, i.e., pulmonary artery smooth muscle cells (PASMCs), and endothelial cell in the microvessels, i.e., pulmonary microvascular endothelial cells (PMVECs), are both equipped with voltage-gated Ca 2ϩ channels. The two major classes of voltage-gated Ca 2ϩ channels are differentiated by their electrophysiological properties: high-voltage-activated channels, which include the L-, N-, P/Q-, and R-subtypes, and low-voltage-activated channels, also known as T-type channels. In addition to their distinct voltage dependence of activation, T-type channels also exhibit a unique rapid inactivation and slow deactivation time course (29). Functionally, the L-type channel has long been considered the predominant source of C...

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“…20) The cardiomyocytes were maintained at 37 C under 5% CO 2 in Dulbecco's modified Eagle's medium (DMEM) supplemented with 10% fetal bovine serum for 24 h, then the medium was changed to serum-free condition containing oxytocin (OT) or [Arg 8 ]-vasopressin (AVP) (10 À8 M to 10 À6 M) for 24-72 h. The spontaneously beating myocytes were subjected to electrophysiological experiments 24-72 h after culture with or without the hormones.…”

Section: Cell Culturementioning

confidence: 99%

“…20,22) Based on this knowledge, we investigated whether decreased levels of Ca V 1.2 mRNA expression occurs as a result of down-regulation of …”

Section: Long-term Effects Of Avp and Ot On Camentioning

confidence: 99%

Nonapeptide Hormones Oxytocin and Vasopressin Distinctly Regulate CaV1.2 L-type Calcium Channel Expression in Cardiomyocytes

et al. 2010

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Background: The neurohypophyseal hormones oxytocin (OT) and [Arg 8 ]-vasopressin (AVP) have recently been implicated in cardiac function. This study was designed to investigate actions of OT and AVP on regulation of the voltage-gated Ca 2þ channel in cardiomyocytes.Methods and Results: Cultured neonatal rat cardiomyocytes were stimulated with OT or AVP (10 À8 M to 10 À6 M) for 24-72 h, followed by real-time PCR and patch clamp studies. Although OT did not exert any modulatory effect on L-type Ca 2þ channel current, as a shortterm effect, stimulation of cardiomyocytes with OT but not AVP decreased the expression of Ca V 1.2 mRNA with a reduced L-type Ca 2þ channel current. A transcription factor CREB mRNA expression was down-regulated by OT treatment, although T-type Ca 2þ channels (Ca V 3.1, Ca V 3.2) were unaffected by OT or AVP.Conclusion: OT but not AVP down-regulates L-type Ca 2þ channel expression through the inhibition of CREB transcriptional, suggesting a novel mechanism of OT action in the cardiac electrophysiology. (J Arrhythmia 2010; 26: 111-118)

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Transcription factors Csx/Nkx2.5 and GATA4 distinctly regulate expression of Ca2+ channels in neonatal rat heart

Cited by 50 publications

References 26 publications

The impact of high salt exposure on cardiovascular development in the early chick embryo

The impact of high salt exposure on cardiovascular development in the early chick embryo

Transcriptional regulation of α_1H T-type calcium channel under hypoxia

Nonapeptide Hormones Oxytocin and Vasopressin Distinctly Regulate CaV1.2 L-type Calcium Channel Expression in Cardiomyocytes

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Transcription factors Csx/Nkx2.5 and GATA4 distinctly regulate expression of Ca2+ channels in neonatal rat heart

Cited by 50 publications

References 26 publications

The impact of high salt exposure on cardiovascular development in the early chick embryo

The impact of high salt exposure on cardiovascular development in the early chick embryo

Transcriptional regulation of α1H T-type calcium channel under hypoxia

Nonapeptide Hormones Oxytocin and Vasopressin Distinctly Regulate CaV1.2 L-type Calcium Channel Expression in Cardiomyocytes

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Transcriptional regulation of α_1H T-type calcium channel under hypoxia