Chromogranin B Regulates Calcium Signaling, Nuclear Factor κB Activity, and Brain Natriuretic Peptide Production in Cardiomyocytes

Abstract

Altered regulation of signaling pathways can lead to pathologies including cardiac hypertrophy and heart failure (HF). We report that neonatal and adult cardiomyocytes express chromogranin B (CGB), a calcium (Ca 2+ ) binding protein which modulates Ca 2+ release by the inositol 1,4,5-trisphosphate receptor (InsP 3 R). Using fluorescent Ca 2+ -indicator dyes, we found that CGB regulates InsP 3 -dependent Ca 2+ release in response to angiotensin-II (ANG-II), an octapeptide hormone that promotes cardiac hypertrophy. ELISA experiments and luciferase reporter assays identified ANG-II as a potent inducer of brain natriuretic peptide (BNP), a hormone that recently emerged as an important biomarker in cardiovascular disease. CGB was found to regulate ANG-II stimulated and basal secretion, expression and promoter activity of BNP that depend on the InsP 3 R. Moreover, we provide evidence that CGB acts via the transcription factor nuclear factor-kappa B (NF-κB) in an InsP 3 /Ca 2+ -dependent manner, but independent of nuclear factor of activated T-cells (NFAT). Invivo experiments further showed that cardiac hypertrophy induced by ANG-II, a condition characterized by increased ventricular BNP production, is associated with up-regulation of ventricular CGB expression. Over-expression of CGB in cardiomyocytes, in turn, induced the BNP promoter. The evidence presented in this study identifies CGB as a novel regulator of cardiomyocyte InsP 3 /Ca 2+ -dependent signaling, NF-κB activity and BNP production. KeywordsChromogranin B (CGB); calcium (Ca 2+ ); inositol 1,4,5-trisphosphate receptor (InsP 3 R); nuclear factor-kappa B (NF-κB); brain natriuretic peptide (BNP)

Chromogranin B in Heart Failure

“…Our findings are in line with another report published during progression of our work demonstrating increased LV CgB production in a mouse model of AngII-induced LV hypertrophy. 22 By immunohistochemistry, Figure 6. Circulating CgB levels during HF.…”

Thirty years of the heart as an endocrine organ: physiological role and clinical utility of cardiac natriuretic hormones

“…Studies using culture of cardiomyocytes (especially from rodents) have demonstrated that several factors (including calcium, catecholamines, endothelins, angiotensin II, and some cytokines) can regulate the expression of ANP and BNP genes throughout the same transcriptional factors, including p38 mitogen-activated protein kinase (MAPK) (19,34,41,50,52,56,60,91), as indicated in Fig. 1.…”

Letter by Heidrich et al Regarding Article, “Inositol 1,4,5-Trisphosphate Receptors and Human Left Ventricular Myocytes”

“…3 CGB, an acidic calcium storage protein, acts as a positive modulator of InsP3R activity. 4 In cardiomyocytes, we showed that CGB functionally interacts with the InsP3R to shape GPCR agonist-driven, InsP3-dependent calcium release from internal stores, being responsible for the differential activation of calcium-dependent transcription factors in cardiomyocyte excitation-transcription coupling.…”

“…4 In cardiomyocytes, we showed that CGB functionally interacts with the InsP3R to shape GPCR agonist-driven, InsP3-dependent calcium release from internal stores, being responsible for the differential activation of calcium-dependent transcription factors in cardiomyocyte excitation-transcription coupling. 3 Therefore, considering that activation of the GPCR/InsP3R axis in cardiomyocytes potentially has both electromechanical and transcriptional implications, we believe it is important to carefully examine all regulatory mechanisms of InsP3R channel activity possibly being involved within a given system. Otherwise, subtle tones and undertones within the complex cardiomyocyte calcium signaling concert can easily be missed.…”