Serglycin is a novel adipocytokine highly expressed in epicardial adipose tissue.

Much recent work has highlighted the key role of adipose tissue as an endocrine organ that secretes a number of adipocytokines, linking adiposity, especially intra-abdominal visceral fat, and the pathogenesis of cardiovascular and metabolic diseases. However, the role of epicardial adipose tissue (EAT), another important visceral fat depot situated in close proximity to epicardial coronary arteries and myocardium, has been less well studied. In this study, we sought to characterize EAT by comparing gene expression profiles of EAT, omental adipose tissue (OAT), and subcutaneous adipose tissue (SCAT) in patients who underwent elective coronary artery bypass graft surgery for critical coronary artery disease (CAD) and identify molecules involved in inflammation. A total of 15,304 probes were detected in all depots, and 231 probes were differentially expressed. Significantly higher expression of pro-inflammatory genes such as interleukin-1ß, -6, and -8, and chemokine receptor 2 was observed in EAT, even when compared with OAT. Among them, serglycin was one of the most abundantly expressed genes in EAT. Serglycin expression was induced during adipocytic differentiation of 3T3L1 cells. Serglycin was secreted from adipocytes, and tumor necrosis factor-α stimulated its expression and secretion in adipocytes. Serglycin was also present in human serum samples. These results suggest that human EAT has strong inflammatory properties in patients with CAD and provide novel evidence that serglycin is an adipocytokine highly expressed in EAT.

PARM-1 promotes cardiomyogenic differentiation through regulating the BMP/Smad signaling pathway.

PARM-1, prostatic androgen repressed message-1, is an endoplasmic reticulum (ER) molecule that is involved in ER stress-induced apoptosis in cardiomyocytes. In this study, we assessed whether PARM-1 plays a role in the differentiation of stem cells into cardiomyocytes. While PARM-1 was not expressed in undifferentiated P19CL6 embryonic carcinoma cells, PARM-1 expression was induced during cardiomyogenic differentiation. This expression followed expression of mesodermal markers, and preceded expression of cardiac transcription factors. PARM-1 overexpression did not alter the expression of undifferentiated markers and the proliferative property in undifferentiated P19CL6 cells. Expression of cardiac transcription factors during cardiomyogenesis was markedly enhanced by overexpression of PARM-1, while expression of mesodermal markers was not altered, suggesting that PARM-1 is involved in the differentiation from the mesodermal lineage to cardiomyocytes. Furthermore, overexpression of PARM-1 induced BMP2 mRNA expression in undifferentiated P19CL6 cells and enhanced both BMP2 and BMP4 mRNA expression in the early phase of cardiomyogenesis. PARM-1 overexpression also enhanced phosphorylation of Smads1/5/8. Thus, PARM-1 plays an important role in the cardiomyogenic differentiation of P19CL6 cells through regulating BMP/Smad signaling pathways, demonstrating a novel role of PARM-1 in the cardiomyogenic differentiation of stem cells.

NFAT5 regulates the canonical Wnt pathway and is required for cardiomyogenic differentiation.

While nuclear factor of activated T cells 5 (NFAT5), a transcription factor implicated in osmotic stress response, is suggested to be involved in other processes such as migration and proliferation, its role in cardiomyogenesis is largely unknown. Here, we examined the role of NFAT5 in cardiac differentiation of P19CL6 cells, and observed that it was abundantly expressed in undifferentiated P19CL6 cells, and its protein expression was significantly downregulated by enhanced proteasomal degradation during DMSO-induced cardiomyogenesis. Expression of a dominant negative mutant of NFAT5 markedly attenuated cardiomyogenesis, which was associated with the inhibition of mesodermal differentiation. TOPflash reporter assay revealed that the transcriptional activity of canonical Wnt signaling was activated prior to mesodermal differentiation, and this activation was markedly attenuated by NFAT5 inhibition. Pharmacological activation of canonical Wnt signaling by [2'Z, 3'E]-6-bromoindirubin-3'-oxime (BIO) restored Brachyury expression in NFAT5DN-expressing cells. Inhibition of NFAT5 markedly attenuated Wnt3 and Wnt3a induction. Expression of Dkk1 and Cerberus1, which are secreted Wnt antagonists, was also inhibited by NFAT5 inhibition. Thus, endogenous NFAT5 regulates the coordinated expression of Wnt ligands and antagonists, which are essential for cardiomyogenesis through the canonical Wnt pathway. These results demonstrated a novel role of NFAT5 in cardiac differentiation of stem cells.