Neuraminidase (NEU)1 forms a multienzyme complex with beta-galactosidase (β-GAL) and protective-protein/cathepsin (PPC) A, which cleaves sialic-acids from cell surface glycoconjugates. We investigated the role of NEU1 in the myocardium after ischemia/reperfusion (I/R). Three days after inducing I/R, left ventricles (LV) of male mice (3 months-old) displayed upregulated neuraminidase activity and increased NEU1, β-GAL and PPCA expression. Mice hypomorphic for neu1 (hNEU1) had less neuraminidase activity, fewer pro-inflammatory (Lin−CD11b+F4/80+Ly-6Chigh), and more anti-inflammatory macrophages (Lin−CD11b+F4/80+Ly-6Clow) 3 days after I/R, and less LV dysfunction 14 days after I/R. WT mice transplanted with hNEU1-bone marrow (BM) and hNEU1 mice with WT-BM showed significantly better LV function 14 days after I/R compared with WT mice with WT-BM. Mice with a cardiomyocyte-specific NEU1 overexpression displayed no difference in inflammation 3 days after I/R, but showed increased cardiomyocyte hypertrophy, reduced expression and mislocalization of Connexin-43 in gap junctions, and LV dysfunction despite a similar infarct scar size to WT mice 14 days after I/R. The upregulation of NEU1 after I/R contributes to heart failure by promoting inflammation in invading monocytes/macrophages, enhancing cardiomyocyte hypertrophy, and impairing gap junction function, suggesting that systemic NEU1 inhibition may reduce heart failure after I/R.
Systemic effects of advanced cancer impact on the heart leading to cardiac atrophy and functional impairment. Using a murine melanoma cancer model (B16F10 melanoma cells stably transduced with a Ganciclovir (GCV)-inducible suicide gene), the present study analysed the recovery potential of cancer-induced cardiomyopathy with or without use of doxorubicin (Dox). After Dox-free tumor elimination and recovery for 70 ± 5 days, cancer-induced morphologic, functional, metabolic and molecular changes were largely reversible in mice previously bearing tumors. Moreover, grip strength and cardiac response to angiotensin II-induced high blood pressure were comparable with healthy control mice. In turn, addition of Dox (12 mg/kg BW) to melanoma-bearing mice reduced survival in the acute phase compared to GCV-alone induced recovery, while long-term effects on cardiac morphologic and functional recovery were similar. However, Dox treatment was associated with permanent changes in the cardiac gene expression pattern, especially the circadian rhythm pathway associated with the DNA damage repair system. Thus, the heart can recover from cancer-induced damage after chemotherapy-free tumor elimination. In contrast, treatment with the cardiotoxic drug Dox induces, besides well-known adverse acute effects, long-term subclinical changes in the heart, especially of circadian clock genes. Since the circadian clock is known to impact on cardiac repair mechanisms, these changes may render the heart more sensitive to additional stress during lifetime, which, at least in part, could contribute to late cardiac toxicity.
Glycoproteins and glycolipids on the cell surfaces of vertebrates and higher invertebrates contain α-keto acid sugars called sialic acids, terminally attached to their glycan structures. The actual level of sialylation, regulated through enzymatic removal of the latter ones by NEU enzymes, highly affects protein-protein, cell-matrix and cell-cell interactions. Thus, their regulatory features affect a large number of different cell types, including those of the immune system. Research regarding NEUs within heart and vessels provides new insights of their involvement in the development of cardiovascular pathologies and identifies mechanisms on how inhibiting NEU enzymes can have a beneficial effect on cardiac remodelling and on a number of different cardiac diseases including CMs and atherosclerosis. In this regard, a multitude of clinical studies demonstrated the potential of N-acetylneuraminic acid (Neu5Ac) to serve as a biomarker following cardiac diseases. Anti-influenza drugs i.e., zanamivir and oseltamivir are viral NEU inhibitors, thus, they block the enzymatic activity of NEUs. When considering the improvement in cardiac function in several different cardiac disease animal models, which results from NEU reduction, the inhibition of NEU enzymes provides a new potential therapeutic treatment strategy to treat cardiac inflammatory pathologies, and thus, administrate cardioprotection.
Cardiac levels of the signal transducer and activator of transcription factor-3 (STAT3) decline with age, and male but not female mice with a cardiomyocyte-specific STAT3 deficiency conditional knockout (CKO) display premature age-related heart failure associated with reduced cardiac capillary density. In the present study, isolated male and female CKO-cardiomyocytes exhibit increased prostaglandin (PG)-generating cyclooxygenase-2 (COX-2) expression. The PG-degrading hydroxyprostaglandin-dehydrogenase-15 (HPGD) expression is only reduced in male cardiomyocytes, which is associated with increased prostaglandin D2 (PGD2) secretion from isolated male but not female CKO-cardiomyocytes. Reduced HPGD expression in male cardiomyocytes derive from impaired androgen receptor (AR)–signaling due to loss of its cofactor STAT3. Elevated PGD2 secretion in males is associated with increased white adipocyte accumulation in aged male but not female hearts. Adipocyte differentiation is enhanced in isolated stem cell antigen-1 (SCA-1)+ cardiac progenitor cells (CPC) from young male CKO-mice compared with the adipocyte differentiation of male wild-type (WT)-CPC and CPC isolated from female mice. Epigenetic analysis in freshly isolated male CKO-CPC display hypermethylation in pro-angiogenic genes (Fgfr2, Epas1) and hypomethylation in the white adipocyte differentiation gene Zfp423 associated with up-regulated ZFP423 expression and a shift from endothelial to white adipocyte differentiation compared with WT-CPC. The expression of the histone-methyltransferase EZH2 is reduced in male CKO-CPC compared with male WT-CPC, whereas no differences in the EZH2 expression in female CPC were observed. Clonally expanded CPC can differentiate into endothelial cells or into adipocytes depending on the differentiation conditions. ZFP423 overexpression is sufficient to induce white adipocyte differentiation of clonal CPC. In isolated WT-CPC, PGD2 stimulation reduces the expression of EZH2, thereby up-regulating ZFP423 expression and promoting white adipocyte differentiation. The treatment of young male CKO mice with the COX inhibitor Ibuprofen or the PGD2 receptor (DP)2 receptor antagonist BAY-u 3405 in vivo increased EZH2 expression and reduced ZFP423 expression and adipocyte differentiation in CKO-CPC. Thus, cardiomyocyte STAT3 deficiency leads to age-related and sex-specific cardiac remodeling and failure in part due to sex-specific alterations in PGD2 secretion and subsequent epigenetic impairment of the differentiation potential of CPC. Causally involved is the impaired AR signaling in absence of STAT3, which reduces the expression of the PG-degrading enzyme HPGD.
31 Cardiac levels of the signal transducer and activator of transcription factor-3 (STAT3) decline 32 with age, and male but not female mice with a cardiomyocyte-specific STAT3 deficiency (CKO) 33 display premature age-related heart failure associated with reduced cardiac capillary density.34 In the present study isolated male and female CKO-cardiomyocytes exhibit increased 35 prostaglandin (PG)-generating cyclooxygenase-2 (COX-2) expression. The PG-degrading 36 hydroxyprostaglandin-dehydrogenase-15 (HPGD) expression is only reduced in male 37 cardiomyocytes, which is associated with increased PGD 2 secretion from isolated male but not 38 female CKO-cardiomyocytes. Reduced HPGD expression in male cardiomyocytes derive from 39 impaired androgen-receptor-(AR)-signaling due to loss of its co-factor STAT3. Elevated PGD 2 40 secretion in males is associated with increased white adipocyte accumulation in aged male 41 but not female hearts. Adipocyte differentiation is enhanced in isolated SCA-1 + -cardiac-42 progenitor-cells (CPC) from young male CKO-mice compared to the adipocyte differentiation 43 of male wildtype (WT)-CPC and CPC isolated from female mice. Epigenetic analysis in freshly 44 isolated male CKO-CPC display hypermethylation in pro-angiogenic genes (Fgfr2, Epas1) and 45 hypomethylation in the white adipocyte differentiation gene Zfp423 associated with 46 upregulated ZFP423 expression and a shift from endothelial to white adipocyte differentiation 47 compared to WT-CPC. The expression of the histone-methyltransferase EZH2 is reduced in 48 male CKO-CPC compared to male WT-CPC whereas no differences in the EZH2 expression 49 in female CPC were observed. Clonally expanded CPC can differentiate into endothelial cells 50 or into adipocytes depending on the differentiation conditions. ZFP423 overexpression is 51 sufficient to induce white adipocyte differentiation of clonal CPC. In isolated WT-CPC, PGD 2 52 stimulation reduces the expression of EZH2 thereby upregulating ZFP423 expression and 53 promoting white adipocyte differentiation.54 Thus, cardiomyocyte STAT3-deficiency leads to age-related and sex-specific cardiac 55 remodeling and failure in part due to sex-specific alterations in PGD 2 secretion and subsequent 56 epigenetic impairment of the differentiation potential of CPC. Causally involved is the impaired 3 57 AR signaling in absence of STAT3, which reduces the expression of the PG degrading enzyme 58 HPGD. 59 4 60 Introduction 61 Men and women experience quite different cardiovascular disease susceptibility profiles and 62 outcome, a feature that is poorly understood. Further, the effects of biologic sex on health, 63 disease susceptibility and mortality are vastly understudied (1, 2). Recent studies showed that 64 genetics contribute to sex-specific differences in fat tissue and cardiovascular and metabolic 65 diseases (3). Pathophysiologically enhanced cardiac fat content is frequently observed in 66 patients with heart failure, in arrhythmogenic right ventricular dysplasia (ARVD), and after 67 ...
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