The SARS-CoV-2 coronavirus has led to a pandemic with millions of people affected. The present study finds that risk-factors for severe COVID-19 disease courses, i.e. male sex, older age and sedentary life style are associated with higher prostaglandin E2 (PGE2) serum levels in blood samples from unaffected subjects. In COVID-19 patients, PGE2 blood levels are markedly elevated and correlate positively with disease severity. SARS-CoV-2 induces PGE2 generation and secretion in infected lung epithelial cells by upregulating cyclo-oxygenase (COX)-2 and reducing the PG-degrading enzyme 15-hydroxyprostaglandin-dehydrogenase. Also living human precision cut lung slices (PCLS) infected with SARS-CoV-2 display upregulated COX-2. Regular exercise in aged individuals lowers PGE2 serum levels, which leads to increased Paired-Box-Protein-Pax-5 (PAX5) expression, a master regulator of B-cell survival, proliferation and differentiation also towards long lived memory B-cells, in human pre-B-cell lines. Moreover, PGE2 levels in serum of COVID-19 patients lowers the expression of PAX5 in human pre-B-cell lines. The PGE2 inhibitor Taxifolin reduces SARS-CoV-2-induced PGE2 production. In conclusion, SARS-CoV-2, male sex, old age, and sedentary life style increase PGE2 levels, which may reduce the early anti-viral defense as well as the development of immunity promoting severe disease courses and multiple infections. Regular exercise and Taxifolin treatment may reduce these risks and prevent severe disease courses.

Aims Peripartum cardiomyopathy (PPCM) is a life-threatening heart disease occurring in previously heart-healthy women. A common pathomechanism in PPCM involves the angiostatic 16 kDa-prolactin (16 kDa-PRL) fragment, which via NF-κB-mediated up-regulation of microRNA-(miR)-146a induces vascular damage and heart failure. We analyse whether the plasminogen activator inhibitor-1 (PAI-1) is involved in the pathophysiology of PPCM. Methods and results In healthy age-matched postpartum women (PP-Ctrl, n = 53, left ventricular ejection fraction, LVEF > 55%), PAI-1 plasma levels were within the normal range (21 ± 10 ng/mL), but significantly elevated (64 ± 38 ng/mL, P < 0.01) in postpartum PPCM patients at baseline (BL, n = 64, mean LVEF: 23 ± 8%). At 6-month follow-up (n = 23), PAI-1 levels decreased (36 ± 14 ng/mL, P < 0.01 vs. BL) and LVEF (49 ± 11%) improved. Increased N-terminal pro-brain natriuretic peptide and Troponin T did not correlate with PAI-1. C-reactive protein, interleukin (IL)-6 and IL-1β did not differ between PPCM patients and PP-Ctrl. MiR-146a was 3.6-fold (P < 0.001) higher in BL-PPCM plasma compared with PP-Ctrl and correlated positively with PAI-1. In BL-PPCM serum, 16 kDa-PRL coprecipitated with PAI-1, which was associated with higher (P < 0.05) uPAR-mediated NF-κB activation in endothelial cells compared with PP-Ctrl serum. Cardiac biopsies and dermal fibroblasts from PPCM patients displayed higher PAI-1 mRNA levels (P < 0.05) than healthy controls. In PPCM mice (due to a cardiomyocyte-specific-knockout for STAT3, CKO), cardiac PAI-1 expression was higher than in postpartum wild-type controls, whereas a systemic PAI-1-knockout in CKO mice accelerated peripartum cardiac fibrosis, inflammation, heart failure, and mortality. Conclusion In PPCM patients, circulating and cardiac PAI-1 expression are up-regulated. While circulating PAI-1 may add 16 kDa-PRL to induce vascular impairment via the uPAR/NF-κB/miR-146a pathway, experimental data suggest that cardiac PAI-1 expression seems to protect the PPCM heart from fibrosis. Thus, measuring circulating PAI-1 and miR-146a, together with an uPAR/NF-κB-activity assay could be developed into a specific diagnostic marker assay for PPCM, but unrestricted reduction of PAI-1 for therapy may not be advised.

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.

The SARS-CoV-2 coronavirus has led to a pandemic with millions of people affected. The present study finds prostaglandin E2 (PGE2) blood levels elevated in COVID-19 patients with positive correlation with disease severity. SARS-CoV-2 induces PGE2 generation and secretion in infected lung epithelial cells by upregulating cyclo-oxygenase (COX)-2 and reducing the PG-degrading enzyme 15-hydroxyprostaglandin-dehydrogenase. Also living human-lung-precision-slices infected with SARS-CoV-2 display upregulated COX-2. PGE2 in serum of COVID-19 patients lowers the expression of Paired-Box-Protein-Pax-5 (PAX5), a master regulator of B-cell survival, proliferation and differentiation, in both human and mouse pre-B-cells, while the PGE2 inhibitor taxifolin directly reduces SARS-CoV-2-induced PGE2 production and attenuates viral replication. Risk-factors for severe disease courses, i.e. older age, male sex and air pollution are associated with higher PGE2 production and lower PAX5 expression in pre-B-cells. Since PGE2 acts broadly immunosuppressive its elevation might reduce the early anti-viral defense and its inhibition may therefore reduce severe disease courses.

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 ...