Abstract
Sustained elevation of sympathetic activity is an important contributor to pathological cardiac hypertrophy, ventricular arrhythmias, and left ventricular contractile dysfunction in chronic heart failure. The orphan nuclear receptor NR4A2 is an immediate early-response gene activated in the heart under β-adrenergic stimulation. The goal of this study was to identify the transcriptional remodeling events induced by increased NR4A2 expression in cardiomyocytes and their impact on the physiological response of those cells to sustained β-adrenergic stimulation. Treatment of adult rat ventricular myocytes with isoproterenol induced a rapid (<4 h) increase in NR4A2 levels that was accompanied by a transient (<24 h) increase in nuclear localization of the transcription factor. Adenovirus-mediated overexpression of NR4A2 to similar levels modulated the expression of genes linked to adrenoceptor signaling, calcium signaling, cell growth and proliferation and counteracted the increase in protein synthesis rate and cell surface area mediated by chronic isoproterenol stimulation. Consistent with those findings, NR4A2 overexpression also blocked the phosphorylative activation of growth-related kinases ERK1/2, Akt, and p70 S6 kinase. Prominent among the transcriptional changes induced by NR4A2 was the upregulation of the dual-specificity phosphatases DUSP2 and DUSP14, two known inhibitors of ERK1/2. Pretreatment of NR4A2-overexpressing cardiomyocytes with the DUSP inhibitor BCI [(E)-2-benzylidene-3-(cyclohexylamino)-2,3-dihydro-1H-inden-1-one] prevented the inhibition of ERK1/2 following isoproterenol stimulation. In conclusion, our results suggest that NR4A2 acts as a novel negative feedback regulator of the β-adrenergic receptor-mediated growth response in cardiomyocytes and this at least partly through DUSP-mediated inhibition of ERK1/2 signaling.
Highlights
Heart failure with reduced left ventricular ejection fraction is a serious health condition with a 50% mortality rate within five years after diagnosis [30]
We found that average FPKM values for cardiomyocyte-specific markers varied between 184 and 2,368 in our adult rat ventricular myocytes (ARVMs) cultures, while FPKM values for nonmyocyte cell markers ranged only between 0 and 6 (Supplemental Fig. S2D)
Impaired growth response of NR4A2-overexpressing cardiomyocytes to chronic -adrenergic stimulation coincided with upregulation of DUSP2 and DUSP14, two known inhibitors of mitogen-activated protein kinases (MAPK)
Summary
Heart failure with reduced left ventricular ejection fraction is a serious health condition with a 50% mortality rate within five years after diagnosis [30]. As the number of Americans diagnosed with heart failure is expected to increase by nearly 40% during the 15 years, the costs of managing the illness will skyrocket, rising from $31 billion in 2012 to $70 billion by 2030 [16]. Increased -adrenergic signaling initially helps maintain the pumping function of the heart, chronic activation eventually leads to inflammation, pathological hypertrophy, impaired calcium homeostasis, and death of cardiomyocytes [22, 41]. Use of -blockers has become a cornerstone therapy for the treatment of patients with chronic heart failure [4, 25]. A better understanding of -adrenergic signaling and of its regulation in cardiomyocytes may provide novel therapeutic insights for improved management of heart failure, increased survival of patients, and decreased burden on the American healthcare system
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