title: Key roles of endothelin-1 and p38 MAPK in the regulation of atrial stretch response.
abstract: Mechanisms regulating stretch response in the left ventricle are investigated in detail but not well understood in atrial myocardium. Hypertrophic growth of atrial myocardium contributes to the pathogenesis of atrial fibrillation. In this study, we sought to elucidate mechanisms of stretch-induced activation of key signaling pathways and hypertrophy-associated genes in rat atria. Stretching of isolated atria induced a rapid increase in phosphorylation of p38 MAPK and ERK and induced a p38 MAPK-dependent increase in DNA binding activity of transcription factors Elk-1 and GATA-4. Inhibition of the ERK pathway had no effect on the cardiac transcription factors studied. Stretch-induced increase in atrial contractile function was substantially enhanced by inhibition of p38 MAPK. p38 MAPK also regulated stretch-induced increase in c-fos, β-myosin heavy chain, B-type natriuretic peptide mRNA levels, and atrial natriuretic peptide secretion in isolated atria. Various autocrine/paracrine factors are known to mediate the stretch response in the left ventricle. Stretching of isolated atria resulted in a robust increase in endothelin-1 (ET-1) mRNA levels, while apelin and adrenomedullin signaling cascades were downregulated. Administration of mixed ET(A/B) receptor antagonist bosentan attenuated the stretch-induced activation of GATA-4 in isolated atria, whereas ANG II receptor type-1 antagonist CV-11974 had no effect. Moreover, analysis of RNA from intact atrial and ventricular myocardium revealed significantly higher mRNA levels of ET(A) receptor and ET converting enzyme-1 in atrial compared with ventricular myocardium. In conclusion, our findings identify the local ET-1 system and p38 MAPK as key regulators of load-induced hypertrophic response in isolated rat atria.
authors.affiliation: Institute of Biomedicine, Department of Pharmacology and Toxicology, University of Oulu, Finland. Risto.Kerkela@oulu.fi
authors.forename: Risto
authors.initials: R
authors.lastname: Kerkelä
authors.forename: Mika
authors.initials: M
authors.lastname: Ilves
authors.forename: Sampsa
authors.initials: S
authors.lastname: Pikkarainen
authors.forename: Heikki
authors.initials: H
authors.lastname: Tokola
authors.forename: Veli-Pekka
authors.initials: VP
authors.lastname: Ronkainen
authors.forename: Theresa
authors.initials: T
authors.lastname: Majalahti
authors.forename: Juhani
authors.initials: J
authors.lastname: Leppäluoto
authors.forename: Olli
authors.initials: O
authors.lastname: Vuolteenaho
authors.forename: Heikki
authors.initials: H
authors.lastname: Ruskoaho
mesh_terms: D000818:Animals; D016275:Atrial Function / Q000502:physiology*; D019332:Endothelin-1 / Q000502:physiology*; D050991:GATA4 Transcription Factor / Q000502:physiology; D008297:Male; D023421:Models, Animal; D009200:Myocardial Contraction / Q000502:physiology*; D018995:Myosin Heavy Chains / Q000502:physiology; D020097:Natriuretic Peptide, Brain / Q000502:physiology; D010766:Phosphorylation; D016760:Proto-Oncogene Proteins c-fos / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D017466:Receptors, Endothelin / Q000502:physiology; D012026:Reflex, Stretch / Q000502:physiology*; D048051:p38 Mitogen-Activated Protein Kinases / Q000502:physiology*
chemical_list: D019332:Endothelin-1; D050991:GATA4 Transcription Factor; C000594638:MYH7 protein, rat; D016760:Proto-Oncogene Proteins c-fos; D017466:Receptors, Endothelin; D020097:Natriuretic Peptide, Brain; D048051:p38 Mitogen-Activated Protein Kinases; D018995:Myosin Heavy Chains