title: 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.
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.
authors.affiliation: Department of Physiology and Pharmacology, University of Western Ontario, London, ON, N6A 5C1, Canada.
authors.forename: Sabzali
authors.initials: S
authors.lastname: Javadov
authors.forename: Delphine
authors.initials: D
authors.lastname: Baetz
authors.forename: Venkatesh
authors.initials: V
authors.lastname: Rajapurohitam
authors.forename: Asad
authors.initials: A
authors.lastname: Zeidan
authors.forename: Lorrie A
authors.initials: LA
authors.lastname: Kirshenbaum
authors.forename: Morris
authors.initials: M
authors.lastname: Karmazyn
mesh_terms: D000818:Animals; D015153:Blotting, Western; D048429:Cell Size / Q000187:drug effects; D002478:Cells, Cultured; D006146:Guanidines / Q000494:pharmacology; D008564:Membrane Potentials / Q000187:drug effects; D008929:Mitochondria, Heart / Q000187:drug effects / Q000378:metabolism* / Q000502:physiology; D033681:Mitochondrial Membrane Transport Proteins / Q000378:metabolism; D000083162:Mitochondrial Permeability Transition Pore; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D032383:Myocytes, Cardiac / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D051381:Rats; D017382:Reactive Oxygen Species / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D017923:Sodium-Hydrogen Exchangers / Q000037:antagonists & inhibitors*; D013450:Sulfones / Q000494:pharmacology
chemical_list: D006146:Guanidines; D033681:Mitochondrial Membrane Transport Proteins; D000083162:Mitochondrial Permeability Transition Pore; C481648:N-(2-methyl-4,5-bis(methylsulfonyl)benzoyl)guanidine; D017382:Reactive Oxygen Species; D017923:Sodium-Hydrogen Exchangers; D013450:Sulfones; C069139:growth factor-activatable Na-H exchanger NHE-1; D020928:Mitogen-Activated Protein Kinases