The adenylosuccinate synthetase‐1 gene is activated in the hypertrophied heart

Abstract

Cardiac hypertrophy is an adaptive response of the heart to stress, including hypertension, mechanical overload, myocardial infarction and genetic mutations in cardiac contractile protein genes [1,2]. In response to stress, intracellular Ca 2+ concentrations increase [3][4][5][6], consistent with a role for Ca 2+ in coordinating physiologic responses with enhanced cardiac output, both acutely and chronically. Thus Ca 2+ provides an important signal for the development of cardiac hypertrophy. Although changes in the expression of contractile and structural genes are well known in cardiac hypertrophy, the genes encoding enzymes of cardiac metabolism and their signal pathways in the cardiac hypertrophy are less well studied. In the current study we were especially interested in changes in cardiomyocyte nucleotide metabolism in response to cardiac hypertrophy, and have focused on the muscle specific isoform of adenylosuccinate synthetase 1 AbstractAdenylosuccinate synthetase 1 (ADSS1) functions as an important component in adenine nucleotide biosynthesis and is abundant in the heart. Here we report that the Adss1 gene is up-regulated in two in vivo rodent models of surgically induced cardiac hypertrophy. In addition, we examined an in vitro hypertrophy system of rat neonatal cardiomyocytes treated with angiotensin II to study Adss1 gene regulation. We show that this stimulus triggers a signaling cascade that results in the activation of the Adss1 gene. The induction of Adss1 gene expression was blocked by cyclosporin A in vitro, suggesting that calcineurin, a calmodulin activated phosphatase, is involved in this signaling pathway. Consistent with this view we provide evidence that the induction of Adss1 by angiotension II requires the presence of an NFAT binding site located 556 base pairs upstream of the Adss1 transcription start site. We propose that ADSS1 plays a role in the development of cardiac hypertrophy through its function in adenine nucleotide biosynthesis.

Characterization and validation of a preventative therapy for hypertrophic cardiomyopathy in a murine model of the disease

“…5 and SI Appendix, Tables S2-S4), pointing to an increased requirement for adenine nucleotides for ATP production in cTnI-G203S hearts. These data are consistent with previous findings demonstrating an increase in adenylosuccinic acid and AMP in surgically or thiazolidinedione-induced cardiac hypertrophy (49,50). Increases in adenylosuccinic acid and AMP production may also provide fumarate for anaplerotic refilling of the TCA cycle.…”

Application of Large-Scale Aptamer-Based Proteomic Profiling to Planned Myocardial Infarctions

“…It is a muscle-specific enzyme that plays a role in purine nucleotide cycle by catalyzing the first step in the conversion of inosine monophosphate to adenosine monophosphate, and mutations in the gene have been reportedly associated with myopathy. 21 Of particular interest are proteins that may have hormone-like functions on other tissues. The mitochondrial ATP synthase-coupling factor 6 (ATP5J), the most substantially increased protein (by 10 minutes) following myocardial injury, is reported to be a vasoactive peptide.…”

Mammalian Target of Rapamycin and Protein Kinase A Signaling Mediate the Cardiac Transcriptional Response to Glutamine

“…Glutamine is a required biosynthetic precursor and intermediate in adenine nucleotide synthesis. Additionally, Adss1 gene expression in cardiomyocytes is stimulated in response to cardiac hypertrophic stimuli (13,40). For these reasons we chose Adss1 as a marker gene to study the cardiac transcriptional response to glutamine.…”

“…The cardiac enhancer region contains essential binding sites for numerous well known cardiac transcription factors including NKX2.5, GATA4, MEF2C, E12, HAND1, and HAND2 (36,53). Adss1 gene expression is also induced by a variety of hypertrophic stimuli including electrical stimulation (13), angiotensin II (40), and aortic banding (40). In these cases Adss1 gene activation is mediated through the action of NFAT transcription factors acting downstream of calcineurin and calmodulin.…”