Antihypertrophic Effect of Na+/H+ Exchanger Isoform 1 Inhibition is Mediated by Reduced Mitogen-activated Protein Kinase Activation Secondary to Improved Mitochondrial Integrity and Decreased Generation of Mitochondrial-derived Reactive Oxygen Species.
From: Department of Physiology and Pharmacology, University of Western Ontario, London, ON, N6A 5C1, Canada.
The Journal of pharmacology and experimental therapeutics
- Publish Date: Jun 2006
- ISSN: 0022-3565
- Volume: 317
- Issue: 3
- Pages: 1036-43
- Medium: Print
- Language: English
- Citation (JAMA): Javadov Sabzali, Baetz Delphine, Rajapurohitam Venkatesh, et al. Antihypertrophic Effect of Na+/H+ Exchanger Isoform 1 Inhibition is Mediated by Reduced Mitogen-activated Protein Kinase Activation Secondary to Improved Mitochondrial Integrity and Decreased Generation of Mitochondrial-derived Reactive Oxygen Species.. J. Pharmacol. Exp. Ther. Jun 2006;317:1036-43
Abstract
Although inhibition of Na+/H+ exchanger isoform 1 (NHE-1) reduces cardiomyocyte hypertrophy, the mechanisms underlying this effect are not known. Recent evidence suggests that this may be associated with improved mitochondrial function. To understand the mechanistic bases for mitochondrial involvement in the antihypertrophic effect of NHE-1 inhibition, we examined the effect of the NHE-1-specific inhibitor N-[2-methyl-4,5-bis(methylsulphonyl)-benzoyl]-guanidine, hydrochloride (EMD, EMD87580; 5 microM) on the hypertrophic phenotype, mitogen-activated protein kinase (MAPK) activity, mitochondrial membrane potential (Deltapsim), permeability transition (MPT) pore opening, and superoxide generation in phenylephrine (PE)-treated neonatal rat cardiomyocytes. EMD significantly suppressed markers of cell hypertrophy, including cell surface area and gene expression of atrial natriuretic peptide and alpha-skeletal actin. EMD inhibited the PE-induced MPT pore opening, prevented the loss in Deltapsim, and attenuated superoxide generation induced by PE. Moreover, the activation of p38 MAPK (p38) and extracellular signal-regulated kinase (ERK) 1/2 MAPKs induced by PE was significantly attenuated in the presence of EMD as well as the antioxidant catalase. To examine the role of MPT and mitochondrial Ca2+ uniport in parallel with EMD, the effects of cyclosporin A (0.2 microM) and ruthenium red (10 microM) were evaluated. Both agents significantly attenuated PE-induced hypertrophy and inhibited both mitochondrial dysfunction and p38 and ERK1/2 MAPK activation. Our results suggest a novel mechanism for attenuation of the hypertrophic phenotype by NHE-1 inhibition that is mediated by a reduction in PE-induced MAPK activation and superoxide production secondary to improved mitochondrial integrity.
Mesh Headings (Keywords): Animals, Blotting, Western, Cell Size, Cells, Cultured, Guanidines, Membrane Potentials, Mitochondria, Heart, Mitochondrial Membrane Transport Proteins, Mitogen-Activated Protein Kinases, Myocytes, Cardiac, Rats, Reactive Oxygen Species, Reverse Transcriptase Polymerase Chain Reaction, Sodium-Hydrogen Antiporter, Sulfones
Check for Full Text / PubMed Unique Identifier (PMID): 16513848
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