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  • MK-571 sodium salt hydrate This study reported reduced TGF a


    This study reported reduced TGF-β and p-Smad2 and p-Smad3 in the cardiac tissue extracts from Mcpt4−/− mice. Yet, we did not detect substantial change in amounts of p-Smad2, p-Smad3, and α-SMA in fibroblasts from these mice. Fibroblasts are the major cell type responsible for cardiac tissue fibrosis. Moderate to minimal reduction of p-Smad2, p-Smad3, and α-SMA in fibroblasts from Mcpt4−/− mice may be responsible for negligible differences in infarct area collagen and α-SMA expression between WT and Mcpt4−/− mice as well. Yet, it remains unexplained what causes reduced p-Smad2 and p-Smad3 in the whole cardiac tissue extracts from Mcpt4−/− mice. mMCP4 activity may affect TGF-β signaling in other cardiac MK-571 sodium salt hydrate such as cardiomyocytes [47,48]. Indeed, cardiomyocyte-specific TGF-β signaling affects neutrophil content in infarcts without affecting cardiac fibrosis [49]. The current study established a role mMCP4 in post-MI cardiomyocyte apoptosis in the ischemic heart, a contributor to cardiac dysfunction. Inhibition of cardiomyocyte apoptosis improves remodeling and preserves cardiac function following coronary artery ligation [50,51]. Here we provide direct evidence of mMCP4 involvement in cardiomyocyte apoptosis in post-MI myocardium in vivo and in cultured adult mouse cardiomyocytes. Deficiency of mMCP4 protected cardiomyocytes from ischemia-induced apoptosis in the myocardium and H2O2-induced apoptosis in cultured cells. IGF-1 inhibits cardiomyocyte apoptosis via multiple mechanisms [52,53]. Prior studies suggested a role of mMCP4 in promoting cardiomyocyte apoptosis by degrading the cardioprotective IGF-1 [23]. Yet, the role of chymase in promoting cardiomyocyte apoptosis can be multifaceted. TGF-β receptor expression and activation on cardiomyocytes can promote these cells undergoing apoptosis by activating downstream p38 MAP kinase and Smad signaling pathways [[54], [55], [56]]. Reduced TGF-β signaling in the myocardium from Mcpt4−/− mice but not in fibroblasts from these mice suggests impaired TGF-β signaling in cardiomyocytes from Mcpt4−/− mice. Our study also suggests that mMCP4 promotes cardiomyocyte apoptosis by regulating cathepsin activity that involves in tBid production [36,40,41]. Reduced expression of CatS, CatK, CatL, and CatB along with reduced Bax and tBid in cardiomyocytes from Mcpt4−/− mice supports this possibility. Cardiomyocyte death is an important signature of post-MI myocardium. mMCP4 expression did not affect post-MI myocardial expression of collagen and α-SMA, suggesting that mMCP4 contributed to post-MI cardiac dysfunction by promoting cardiomyocyte apoptosis MK-571 sodium salt hydrate but not fibrosis. Therefore, post-MI cardiac dysfunction may not have to associate with myocardial expression of collagen or α-SMA [57,58].
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    Introduction Pyrimidine nucleotides are essential for a vast number of biological processes such as the synthesis of RNA and DNA. Moreover pyrimidine-activated sugars are also involved in synthesis of phospholipids, glycogen, signal transduction, the sialylation and glycosylation of proteins and lipids and glucuronidation in detoxification processes [1]. In addition, pyrimidines play an important role in the regulation of the central nervous system and metabolic changes affecting the levels of pyrimidines may lead to abnormal neurological activity [2,3]. Pyrimidines can be synthesized de novo in mammalian cells through multistep processes (Fig. 1). In addition to the de novo synthesis, pyrimidine nucleotides can also be synthesized via the salvage of the nucleosides uridine and cytidine. Opposing the action of the enzymes involved in anabolism of pyrimidines are those facilitating the degradation of the pyrimidine nucleosides and pyrimidine bases. The uptake of pyrimidine nucleosides from the extracellular space is mediated by nucleoside-transport proteins that facilitate diffusion or active transport of nucleosides across the plasma membrane. They are encoded by genes belonging to SLC28 and SLC29 families [4,5]. SLC29 genes encode human Equilibrative Nucleoside Transporter (hENT) proteins. This family has four members with only hENT1 (SLC29A1) and hENT2 (SLC29A2) being plasma membrane nucleoside transporters. The SLC28 gene family encodes three human Concentrative Nucleoside Transporter (hCNT) proteins, hCNT1, hCNT2, and hCNT3. They all are Na+-coupled nucleoside transporters showing substrate preference for pyrimidines (hCNT1), purines and uridine (hCNT2), and for both purine and pyrimidine nucleosides (hCNT3).