Activation of Na+-H+ Antiporter (NHE-1) gene expression during growth, hypertrophy and proliferation of the rabbit cardiovascular system

Syin ichi Takewaki, Makoto Kuro-o, Yukio Hiroi, Tsutomu Yamazaki, Tsuyoshi Noguchi, Akira Miyagishi, Ken ichi Nakahara, Masanori Aikawa, Ichiro Manabe, Yoshio Yazaki, Ryozo Nagai

Research output: Contribution to journalArticle

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Abstract

S.-I. Takewaki, M. Kuro-o, Y. Hiroi, T. Yamazaki, T. Noguchi, A. Miyagishi, K.-I. Nakahara, M. Aikawa, I. Manabe, Y. Yazaki and R. Nagai, Activation of Na+-H+ Antiporter (NHE-1) Gene Expression during Growth, Hypertrophy and Proliferation of the Rabbit Cardiovascular System, Journal of Molecular and Cellular Cardiology (1995) 27, 729-742, The Na+-H+ antiporter is a unique transmembrane protein with multiple roles in cellular functions through intracellular alkalization. It participates in the regulation of intracellular pH, cell volume and intracellular signalling in response to various mitogenic stimuli. To clarify its role as a subcellular signal in cardiovascular remodeling like vascular hyperplasia or cardiac hypertrophy, we determined mRNA levels of the Na+-H+ antiporter isoform, NHE-1, in vascular smooth muscles and pressure-overloaded hearts in rabbits. The NHE-1 mRNA levels in rabbit aortas and hearts were de-velopmentally regulated with high levels at embryonic and neonatal stages than in adults. In primary-cultured smooth muscle cells (SMC), the mRNA levels were increased during exponential growth, but decreased to initial levels at coniuency. Growth of a mutant SMC line, C5, which is deficient in Na+-H+ antiporter activity, was markedly reduced in bicarbonate-free medium. However, when the activity was restored by transfecting cells with a full-length NHE-1 cDNA in an expression vector, the growth rate of C5 was accelerated again. After balloon injury to the vascular wall, the NHE-1 mRNA levels of the injured arteries were also increased, suggesting that Na+-H+ antiporter contributes to the network of the growth promoting systems in smooth muscle cells in vivo. Pressure-overload on the ventricle increased the NHE-1 mRNA levels in hearts approximately two-fold of sham-operated rabbits after 3 days and remained for at least; two weeks (P<0.05). We further demonstrated that 3-m.ethylsulfonyl-4-piperidino-benzoyl guanidine mesylate (Hoe 694), a potent antagonist of Na+-H+ antiporter, partially inhibited stretch-induced activation of mitogen-activated kinase (MAP kinase) in the cultured cardiomyocytes. From these results, we conclude that activation of the Na+-H+ antiporter and its gene expression is involved in molecular mechanisms of both cardiac hypertrophy and vascular smooth muscle cell proliferation, indicating a potential target in developing new therapeutics for cardiovascular diseases.

Original languageEnglish (US)
Pages (from-to)729-742
Number of pages14
JournalJournal of Molecular and Cellular Cardiology
Volume27
Issue number1
StatePublished - Jan 1995

Fingerprint

Sodium-Hydrogen Antiporter
Cardiovascular System
Hypertrophy
Rabbits
Gene Expression
Growth
Smooth Muscle Myocytes
Messenger RNA
Cardiomegaly
Vascular Smooth Muscle
Pressure
Mesylates
Vascular System Injuries
Guanidine
Mitogen-Activated Protein Kinase Kinases
Bicarbonates
Cardiology
Cell Size
Mitogens
Cardiac Myocytes

Keywords

  • Cardiac hypertrophy
  • mRNA expression
  • Na-H Antiporter
  • NHE-1
  • Smooth muscle cell proliferation

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine
  • Molecular Biology

Cite this

Takewaki, S. I., Kuro-o, M., Hiroi, Y., Yamazaki, T., Noguchi, T., Miyagishi, A., ... Nagai, R. (1995). Activation of Na+-H+ Antiporter (NHE-1) gene expression during growth, hypertrophy and proliferation of the rabbit cardiovascular system. Journal of Molecular and Cellular Cardiology, 27(1), 729-742.

Activation of Na+-H+ Antiporter (NHE-1) gene expression during growth, hypertrophy and proliferation of the rabbit cardiovascular system. / Takewaki, Syin ichi; Kuro-o, Makoto; Hiroi, Yukio; Yamazaki, Tsutomu; Noguchi, Tsuyoshi; Miyagishi, Akira; Nakahara, Ken ichi; Aikawa, Masanori; Manabe, Ichiro; Yazaki, Yoshio; Nagai, Ryozo.

In: Journal of Molecular and Cellular Cardiology, Vol. 27, No. 1, 01.1995, p. 729-742.

Research output: Contribution to journalArticle

Takewaki, SI, Kuro-o, M, Hiroi, Y, Yamazaki, T, Noguchi, T, Miyagishi, A, Nakahara, KI, Aikawa, M, Manabe, I, Yazaki, Y & Nagai, R 1995, 'Activation of Na+-H+ Antiporter (NHE-1) gene expression during growth, hypertrophy and proliferation of the rabbit cardiovascular system', Journal of Molecular and Cellular Cardiology, vol. 27, no. 1, pp. 729-742.
Takewaki, Syin ichi ; Kuro-o, Makoto ; Hiroi, Yukio ; Yamazaki, Tsutomu ; Noguchi, Tsuyoshi ; Miyagishi, Akira ; Nakahara, Ken ichi ; Aikawa, Masanori ; Manabe, Ichiro ; Yazaki, Yoshio ; Nagai, Ryozo. / Activation of Na+-H+ Antiporter (NHE-1) gene expression during growth, hypertrophy and proliferation of the rabbit cardiovascular system. In: Journal of Molecular and Cellular Cardiology. 1995 ; Vol. 27, No. 1. pp. 729-742.
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