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, ␤-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 ETA 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.

Cardiac Atrial Circadian Rhythms in PERIOD2::LUCIFERASE and per1:luc Mice: Amplitude and Phase Responses to Glucocorticoid Signaling and Medium Treatment

“…Furthermore, several components of the intracellular signaling cascade responsible for conveying the atrial myocardial stretch response for atrial natriuretic peptide secretion, are shared with those regulating the circadian clock, e.g. protein kinase C and mitogen-activated protein kinase (MAPK) [22], [32], [46]–[48].…”

Mitogen-Activated Protein Kinases Pathways Mediate the Sunitinib-Induced Hypertrophy in Rat Cardiomyocyte H9c2 Cells

“…Importantly, a cross talk between MAPK signaling pathway and hypertrophic genes has been reported. In that, inhibition of the p38 MAPK in cardiac hypertrophied rat resulted in a significant decrease in the expression of b-MHC and several natriuretic peptides, but not in healthy rats [20]. In addition, it has been reported that activation of ERK MAPK induced the expression of hypertrophic genes through stimulation of cardiac transcriptional factor GATA4 [21][22][23][24].…”

Atrial natriuretic peptide in cardiovascular biology and disease (NPPA)

“…Mechanical stretch of the atrial wall is one of the most potent stimuli for ANP expression and release (Edwards et al, 1988). The signaling molecules in this process include integrins, p38 MAPK and focal adhesion kinase (Kerkela et al, 2011; Peng et al, 2008). To date, many growth factors and vasoactive molecules have been reported to enhance ANP expression and secretion (Ogawa and de Bold, 2014; Potter et al, 2006).…”