Inhibition of the Notch1 pathway induces peripartum cardiomyopathy

Increased expression and activity of cardiac and circulating cathepsin D and soluble fms‐like tyrosine kinase‐1 (sFlt‐1) have been demonstrated to induce and promote peripartum cardiomyopathy (PPCM) via promoting cleavage of 23‐kD prolactin (PRL) to 16‐kD PRL and neutralizing vascular endothelial growth factor (VEGF), respectively. We hypothesized that activation of Hes1 is proposed to suppress cathepsin D via activating Stat3, leading to alleviated development of PPCM. In the present study, we aimed to investigate the role of Notch1/Hes1 pathway in PPCM. Pregnant mice between prenatal 3 days and postpartum 3 weeks were fed with LY‐411575 (a notch inhibitor, 10 mg/kg/d). Ventricular function and pathology were evaluated by echocardiography and histological analysis. Western blotting analysis was used to examine the expression at the protein level. The results found that inhibition of Notch1 significantly promoted postpartum ventricular dilatation, myocardial hypertrophy and myocardial interstitial fibrosis and suppressed myocardial angiogenesis. Western blotting analysis showed that inhibition of Notch1 markedly increased cathepsin D and sFlt‐1, reduced Hes1, phosphorylated Stat3 (p‐Stat3), VEGFA and PDGFB, and promoted cleavage of 23k‐D PRL to 16‐kD PRL. Collectively, inhibition of Notch1/Hes1 pathway induced and promoted PPCM via increasing the expressions of cathepsin D and sFlt‐1. Notch1/Hes1 was a promising target for prevention and therapeutic regimen of PPCM.     

Description and genome analysis of Microvirga antarctica sp. nov., a novel pink-pigmented psychrotolerant bacterium isolated from Antarctic soil

Antonie van Leeuwenhoek - A novel pink-pigmented bacterium, designated strain 3D7T, was isolated during an investigation of potential psychrotolerant species from Antarctic soil. Cells of the...     

Congestive heart failure in COX2 deficient rats

Non-steroidal anti-inflammatory drugs (NSAIDs) inhibit prostaglandin (PG) formation by targeting cyclooxygenase (COX) 1 and 2.Long-term use of NSAIDs that selectively inhibit COX2 increases the risk for thrombotic events,cardiac failure,and hypertension.However,the underlying mechanisms remain unclear.In this study,COX1- and COX2-deficient rats were created via Cas9/RNA-mediated gene targeting.DNA genotyping and Western blot analysis confirmed successful generation of COX1~(-/-)and COX2~(-/-)rats.Adult COX1~(-/-)rats grew normally,while more than 70%of COX2~(-/-)rats after wean died within 2 months.Echocardiography showed markedly reduced left ventricular ejection fraction and fractional shortening in adult COX2~(-/-)rats compared to those in wildtype (WT) controls.Histological analysis revealed accumulation of inflammatory cells and severe interstitial and perivascular fibrosis in COX2~(-/-)cardiac tissues.Moreover,cardiac ATP and acetyl-Co A production was dramatically decreased in COX2~(-/-)rats.Consistently,the expression of genes related to mitochondrial oxidation,such as those that encode for subunits of pyruvate dehydrogenase complex and acyl Co A dehydrogenases,were downregulated,while glycolytic hexokinase 1 (HK1) was upregulated in COX2~(-/-)heart tissues.These observations indicate that COX2-deficient rats developed spontaneously heart failure,likely as a result of dysregulated cardiac energy metabolism.     

Leptin gene-targeted editing in ob/ob mouse adipose tissue based on the CRISPR/Cas9 system

Gene therapy has become the most effective treatment for monogenic diseases. Congenital LEPTIN deficiency is a rare autosomal recessive monogenic obesity syndrome caused by mutations in the Leptin gene. Ob/ob mouse is a monogenic obesity model, which carries a homozygous point mutation of C to T in Exon 2 of the Leptin gene. Here, we attempted to edit the mutated Leptin gene in ob/ob mice preadipocytes and inguinal adipose tissues using CRISPR/Cas9 to correct the C to T mutation and restore the production of LEPTIN protein by adipocytes. The edited preadipocytes exhibit a correction of 5.5% of Leptin alleles and produce normal LEPTIN protein when differentiated into mature adipocytes. The ob/ob mice display correction of 1.67% of Leptin alleles, which is sufficient to restore the production and physiological functions of LEPTIN protein, such as suppressing appetite and alleviating insulin resistance. Our study suggests CRISPR/Cas9-mediated in situ genome editing as a feasible therapeutic strategy for human monogenic diseases, and paves the way for further research on efficient delivery system in potential future clinical application.