1. Key roles of endothelin-1 and p38 MAPK in the regulation of atrial stretch response
- Author
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Risto Kerkelä, Heikki Tokola, Theresa Majalahti, Heikki Ruskoaho, Veli-Pekka Ronkainen, Sampsa Pikkarainen, Mika Ilves, Olli Vuolteenaho, and Juhani Leppäluoto
- Subjects
Male ,Reflex, Stretch ,medicine.medical_specialty ,Physiology ,Biology ,p38 Mitogen-Activated Protein Kinases ,Muscle hypertrophy ,Rats, Sprague-Dawley ,Physiology (medical) ,Internal medicine ,Natriuretic Peptide, Brain ,Renin–angiotensin system ,medicine ,Animals ,Phosphorylation ,Endothelin-1 ,Myosin Heavy Chains ,Receptors, Endothelin ,Atrial fibrillation ,Atrial Function ,medicine.disease ,Myocardial Contraction ,Endothelin 1 ,GATA4 Transcription Factor ,Rats ,Cell biology ,medicine.anatomical_structure ,Endocrinology ,Ventricle ,Models, Animal ,Circulatory system ,cardiovascular system ,Signal transduction ,Proto-Oncogene Proteins c-fos ,Immediate early gene - 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 ETA/Breceptor 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 ETAreceptor 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.
- Published
- 2011